Liens entre le criblage virtuel (vHTS) de cibles thrapeutiques potentielles et la conception de molcules rellesSuzanne SiroisProfesseure AssocieDpartement de ChimieUQM

BiologiquesGnomique, protomique, chemognomiqueChimiques Catalyse, sparations, ractionsDcouvertes dagents thrapeutiques optimisation, dveloppement, biodisponibilitPolymres Gels, adhsifs, lubrifiants, peinturesMatriauxPrdiction de structures, spectroscopieNano-technologieChamps dapplications in silico

PrsentationChimiothques et CibliothquesExemple dapplication: SARS-CoV Mpro Interaction protine-protine: boucle V3 de gp120 VIH-1:CCR5 eProjet denvergure Criblage grande chelle sur cibles thrapeutiques

Projet du Gnome HumainSelon lInternational Human Genome Sequencing Consortium, on estime le nombre de gnes encodant les protines humaines entre 20,000-25,000

Lincoln D. Stein. Human genome: End of the beginning. Nature 431, 915 - 916 2004

LUnivers Chimique10100-400 molcules

Lunion des deux: ChimiognomiqueDcouverte et mise au point de molcules thrapeutiquesIdentification de la fonction des protinesIntgre les informations gnomiquebiologiquechimique pharmacologique et pharmacocintiqueSert comprendre la base molculaire de l'efficacit d'une molcules et prdire sa toxicit potentielle et autres effets indsirablesInteractions protine-protine

Chimiothques (~5M)

Fournisseur

Nombre

Fournisseur

Nombre

ACB

57314

KeyOrganics

34736

ACD

87657

Maybridge

68787

ACDvirt

145824

MaybridgeHTS

50000

Akos

85925

Menai

4512

Aldrich

129080

NCI_DTP

126705

Asinex

274275

NCI_aug2D

250251

Bionet

34681

Otava

86109

ChemDiv

174467

Peakdale

3770

ChembridgeDVS

30000

Pharmacore

10000

ChembridgeEx

280244

Princeton

204215

ChembridgeHTS

50000

Ryan

60350

Chemstar

107028

SPECS

172469

Comgenex

119247

TalonHTS

25169

Enamine

234115

Timtec

109876

Evotec

122998

Toslab

11743

EvotecLeadDisc

76817

Tripos

87467

GandJ

1867

WDI

4413

IBS

195899

WorldMolecules

19401

IFlab

109400

Filtrage: proprits physico-chimiques

Chart5

0.275482847929.31535801218.520060982420.849650349718.174157303420.35014824423.141755039423.88255416195.486666666716.040855910228.768278164221.8601788494

0.094835552214.6445497638.45052615928.513986014MW >50007.885643295617.89864448182.83637400230.00333333332.813661738915.40919732738.5062090438

0.00018252960.01473037020.01041163130.013986014MW 100.01404494380.20670647680.0253932938000.01678499050.07803999980.3258390355

0.00053618080.05571922630.09667943330.0979020979HBdon >50.13342696630.23176180730.00483681790.00285062710.00666666670.03294831470.04727970790.3367003367

0.02031782975.07429230182.41252370512.6818181818RotBond >150.66713483152.1161314578.37132250690.36202964650.060.97042111682.72627327673.3072662105

0.00452901650.54374279490.18889673890.6993006993cycles >60.03511235960.67075207750.40750190450.03135689850.03333333330.19209489110.50355737080.6028022157

0.00420958971.69014986550.68493660060.3041958042SingleChain>70.04213483150.92548127110.03023011160.25655644240.12666666670.11687326710.42209956081.0481155642

0.0110658590.66478801080.34878964790.2727272727ring size >70.09831460670.30170793840.00120920450.04561003420.30333333330.22846237050.20563824760.5403497339

0.00292047412.04431920070.16063659690.3531468531halogene >70.03511235960.325197310700.59578107180.050.08361411930.06322948890.3249339271

0.001562910.76726015110.02528539030.041958042CF3CF2CF20.04915730340.126842610800.00570125430.02333333330.02051498840.00854452550.1321458311

0.102376307711.62482387618.40553303839.3216783217Reactive0.035112359611.89032029064.730407864715.801026225812.15666666679.01820238977.003093118213.3965099019

ACD 87657,0000000

Akos Lithuania 156140,0000

Akos Re-synthetic 134465,0000

Akos OWHp 28600,0000

#REF!

Asinex Pre-formated 14240,0000

Asinex Gold 191576,0000

Asinex Platinum 82699,0000

Bionet 35080,0000

Chembridge DVS 30000,0000

Chembridge Express 321716,0000

Chemical Diversity Clab 175551,0000

Chemical Diversity IDC 110484,0000

Chart6

123.691573970720.462563.023807726836.309767993125.572255264435.565044195934.768858030223.8350294591.638089015327.26644322226.299817184623.6958774758

logP >610.15175950059.272539.199308997318.115684397610.792477093718.81354387718.17184019258.08784145690.766211159811.73374846799.184643510110.8302625518

MW >5009.70240802778.11539.14396169330.04877159412.40073943162.125571162654.67975089031.39260846281.220526904212.56905194813.76965265082.8385536619

Weight >6001.78086534621.584.00345501356.14339760242.010126989219.265266802917.47670693830.16068559190.46809835681.68919507652.96983546620.2216720405

MW 100.29221629520.05250.00251578660.0410228360.15672721430.18355311980.0674807720.0535618640.38233987920.15509459610.06946983550.008636573

HBdon >50.34597306650.5100.00364647430.09885870440.54805576890.07723702820.10712372790.40633183430.13011681470.07038391220.0028788577

RotBond >152.91664943692.8820.52294816644.74315146542.383861115625.448793886822.66378315091.23192287091.04390527773.20296480463.64625228520.356978351

cycles >60.62302719540.710.26667337540.49500888830.81658897282.77022013362.529309419700.25370216281.10657380350.29707495430.0287885767

SingleChain>70.87664888561.29255.19677643880.58708236470.35364089370.05858078290.05691149451.49973219070.17049602091.15362497310.44789762340.2533394749

ring size >70.34045955150.487500.0756643420.221829287900.00569114940.48205677560.10464576130.3520124540.15356489950.043182865

halogene >70.27843250770.3350.07966657440.0756643420.2274553930.07290052980.09674954060.21424745580.00204186850.21318245980.05210237660.6016812529

CF3CF2CF20.08545948260.1325000.066709532200.005691149400.00255233560.10339639740.0127970750.0057577153

Reactive12.155922204311.377.596836817715.779205980214.659218775111.617220146610.922128815113.6582753082.827987891713.64077303337.300731261415.0708198987

#REF!

ChemStar 72549,0000000

ChemStar Plated 40000,0000

Comgenex 119247,0000

Enamine RS 109695,0000

Enamine S 124420,0000

Evotec Lead Discovery 76817,0000

Evotec Screening 122998,0000

G & J 1867,0000

IBS n 195899,0000

IBS S 172153,0000

IFlab 109400,0000

KeyOrganics 34736,0000

Chart7

13.68342604679.833430742318.010035230113.32003546123.048407027319.881818181810.417899846116.916687448414.350132626129.254958820125.40410841524.7535211268

5.32059301064.20075978969.34130457994.898049645412.30860151517.69090909095.4267787385.95062249424.8275862069logP >613.58995994919.80486252231.3204225352

2.10002395461.82641729986.11722002781.994680851110.71831515614.66818181825.05741683445.86813481945.3846153846MW >50017.798271989411.39975026320.088028169

0.31540283730.54792518992.14583110920.22163120574.416268199602.39690619940.97354639450.1856763926Weight >6004.26179242481.59880518080

00.72326125070.170812426600.01611776720.01363636361.328282230416.94450305970.0265251989MW 100.07962635040.18314031780.088028169

0.16369008010.0730566920.66189815310.17730496450.38145382260.29772727272.30456572350.11509908110HBdon >50.21392153830.1674705580.088028169

0.80381145030.81823495033.52300629870.33244680854.0348143771.34318181825.6398721441.73032285292.7055702918RotBond >154.82274223643.36459123962.2007042254

0.07718719220.13150204560.80068324970.02216312060.73604469990.31590909090.80975494260.3059717240.0265251989cycles >61.58064247770.35942511570

0.29677144610.63559322031.35582363620.17730496452.10605490791.06136363642.75442958050.35680715150.2387267905SingleChain>70.95908156350.68506231186.514084507

0.15570519820.23378141441.62271805270.02216312060.46204265840.55454545451.12465964250.16881198570.0265251989ring size >70.34940517930.09744631880.088028169

0.41787548910.86206896551.03555033630.28812056740.34384569920.25681818180.32437551790.09591590090.0530503979halogene >70.10933767510.09989471880

0.00931569560.27030976040.61919504640.13297872340.18804061680.13409090910.11443905130.05754954060CF3CF2CF20.05348038460.06120999930

10.163423917435.359438924623.45468132810.022163120617.1815397846.797727272728.686318614110.240940743211.9098143236Reactive20.750389218411.229341625223.9436619718

Maybridge 75142,0000000

Maybridge Intermediate 13688,0000

MDPI 9367,0000

Menai 4512,0000

Nanosyn Explore 18613,0000

Nanosyn Pharma 44000,0000

NCI DTP 126705,0000

Otava 104258,0000

Peakdale 3770,0000

#REF!

Pharmeks 84143,0000

Princeton 204215,0000

Ryan Intermediate 1136,0000

Chart8

15.93204309798.717280181129.614473400823.606978826720.15383285828.19231282141120.677083333322.747217679241.531124925512.563704005722.2293024852

7.04731989065.627980376713.88470098369.841416563210.714285714311.8572033235logP >6logP >66.39583333339.784993418216.78446734222.84502089498.75447282

6.14719492016.818415726116.060018666110.92463676026.42770719910.5172523758MW >500MW >5005.27083333339.666320954238.388827386511.4399653459.1564139013

1.60772790224.62451542083.20913202671.71870937922.80442485521.6739240095Weight >600Weight >6000.82291666672.078263991410.21033807370.27774946491.6273712073

0.094572229514.84613537340.03589633140.11265490050.39538501430.0011596287MW 100.13541666670.0618293510.119219960800.2842997892

0.99638598984.36378606470.10768899420.2715271960.63736928530.1072656535HBdon >5HBdon >50.26041666670.3041605170.3150813250.00382224030.3823341993

3.85381835389.16154928135.4562423724.26066610826.63944343622.3059216439RotBond >15RotBond >151.63541666672.722485938813.23341565193.04377739271.7597176609

0.59276522441.32423067690.55998276980.41740084921.27257799670.6360563348cycles >6cycles >60.27083333330.74095496431.4136081070.10192640911.1470025979

2.60242510224.60393152422.13224208492.34264421274.22392187360.6951973978SingleChain>7SingleChain>701.08799712790.34914417100.2303808637

0.68564866421.53006964220.76100222560.27441578321.90562613430.5525630693ring size >7ring size >70.093750.54948342570.05960998040.03567424320.2401843047

0.12159286660.6586846890.26563285230.21664403940.44939936050.1072656535halogene >7halogene >700.33407794490.19586136420.16053409440.0735258076

0.04221974530.34649559160.15794385810.10543343250.04753262470.0365283036CF3CF2CF2CF3CF2CF200.11069448320.10218853790.00254816020.039213764

16.176917620825.944286253415.794385813818.026228371719.533748163511.6820993918ReactiveReactive8.6562512.07966013817.542365664718.030781775614.464977207

Ryan Labo 59214

Sigma Aldrich 58298,0000000

Sigma Aldrich L 13929,0000

Sigma Aldrich R 69238,0000

Sigma Aldrich S 46284,0000

SPECS 172469,0000

#REF!

#REF!

Timtec MaxiVerse 9600,0000

Timtec Stock 100276,0000

Toslab 11743,0000

Tripos 78488,0000

World Molecules 20401,0000

Rules1

0.275482847929.31535801218.520060982420.84965034978.174157303420.35014824423.141755039423.88255416195.486666666716.040855910228.768278164221.8601788494

0.094835552214.6445497638.45052615928.51398601407.885643295617.89864448182.83637400230.00333333332.813661738915.40919732738.5062090438

0.00018252960.01473037020.01041163130.0139860140000.0313568985000.0005696350.0054306506

0.00003422430.09991033690.06767560330.08041958040.01404494380.20670647680.0253932938000.01678499050.07803999980.3258390355

0.00053618080.05571922630.09667943330.09790209790.13342696630.23176180730.00483681790.00285062710.00666666670.03294831470.04727970790.3367003367

0.02031782975.07429230182.41252370512.68181818180.66713483152.1161314578.37132250690.36202964650.060.97042111682.72627327673.3072662105

0.00452901650.54374279490.18889673890.69930069930.03511235960.67075207750.40750190450.03135689850.03333333330.19209489110.50355737080.6028022157

0.00420958971.69014986550.68493660060.30419580420.04213483150.92548127110.03023011160.25655644240.12666666670.11687326710.42209956081.0481155642

0.0110658590.66478801080.34878964790.27272727270.09831460670.30170793840.00120920450.04561003420.30333333330.22846237050.20563824760.5403497339

0.00292047412.04431920070.16063659690.35314685310.03511235960.325197310700.59578107180.050.08361411930.06322948890.3249339271

0.001562910.76726015110.02528539030.0419580420.04915730340.126842610800.00570125430.02333333330.02051498840.00854452550.1321458311

0.102376307711.62482387618.40553303839.32167832170.035112359611.89032029064.730407864715.801026225812.15666666679.01820238977.003093118213.3965099019

ACD 87657,0000000

Akos Lithuania 156140,0000

Akos Re-synthetic 134465,0000

Akos OWHp 28600,0000

Asinex Pre-formated 14240,0000

Asinex Gold 191576,0000

Asinex Platinum 82699,0000

Bionet 35080,0000

Chembridge DVS 30000,0000

Chembridge Express 321716,0000

Chemical Diversity Clab 175551,0000

Chemical Diversity IDC 110484,0000

Filtres

%

Rules2

23.691573970720.462563.023807726836.309767993125.572255264435.565044195934.768858030223.8350294591.638089015327.26644322226.299817184623.6958774758

10.15175950059.272539.199308997318.115684397610.792477093718.81354387718.17184019258.08784145690.766211159811.73374846799.184643510110.8302625518

9.70240802778.11539.14396169330.04877159412.40073943162.125571162654.67975089031.39260846281.220526904212.56905194813.76965265082.8385536619

1.78086534621.584.00345501356.14339760242.010126989219.265266802917.47670693830.16068559190.46809835681.68919507652.96983546620.2216720405

0.024810817510.035000.014467127500000.006970543600.0287885767

0.29221629520.05250.00251578660.0410228360.15672721430.18355311980.0674807720.0535618640.38233987920.15509459610.06946983550.008636573

0.34597306650.5100.00364647430.09885870440.54805576890.07723702820.10712372790.40633183430.13011681470.07038391220.0028788577

2.91664943692.8820.52294816644.74315146542.383861115625.448793886822.66378315091.23192287091.04390527773.20296480463.64625228520.356978351

0.62302719540.710.26667337540.49500888830.81658897282.77022013362.529309419700.25370216281.10657380350.29707495430.0287885767

0.87664888561.29255.19677643880.58708236470.35364089370.05858078290.05691149451.49973219070.17049602091.15362497310.44789762340.2533394749

0.34045955150.487500.0756643420.221829287900.00569114940.48205677560.10464576130.3520124540.15356489950.043182865

0.27843250770.3350.07966657440.0756643420.2274553930.07290052980.09674954060.21424745580.00204186850.21318245980.05210237660.6016812529

0.08545948260.1325000.066709532200.005691149400.00255233560.10339639740.0127970750.0057577153

12.155922204311.377.596836817715.779205980214.659218775111.617220146610.922128815113.6582753082.827987891713.64077303337.300731261415.0708198987

ChemStar 72549,0000000

ChemStar Plated 40000,0000

Comgenex 119247,0000

Enamine RS 109695,0000

Enamine S 124420,0000

Evotec Lead Discovery 76817,0000

Evotec Screening 122998,0000

G & J 1867,0000

IBS n 195899,0000

IBS S 172153,0000

IFlab 109400,0000

KeyOrganics 34736,0000

Druggable Rules

%

Rules3

13.68342604679.833430742318.010035230113.32003546123.048407027319.881818181810.417899846116.916687448414.35013262629.254958820125.40410841524.7535211268

5.32059301064.20075978969.34130457994.898049645412.30860151517.69090909095.4267787385.95062249424.827586206913.58995994919.80486252231.3204225352

2.10002395461.82641729986.11722002781.994680851110.71831515614.66818181825.05741683445.86813481945.384615384617.798271989411.39975026320.088028169

0.31540283730.54792518992.14583110920.22163120574.416268199602.39690619940.97354639450.18567639264.26179242481.59880518080

00.72326125070.170812426600.01611776720.01363636361.328282230416.94450305970.02652519890.0011884530.00636583992.5528169014

0.17566740310.17533606081.088929219600.46741524740.12272727271.51690935640.008632431100.07962635040.18314031780.088028169

0.16369008010.0730566920.66189815310.17730496450.38145382260.29772727272.30456572350.115099081100.21392153830.1674705580.088028169

0.80381145030.81823495033.52300629870.33244680854.0348143771.34318181825.6398721441.73032285292.70557029184.82274223643.36459123962.2007042254

0.07718719220.13150204560.80068324970.02216312060.73604469990.31590909090.80975494260.3059717240.02652519891.58064247770.35942511570

0.29677144610.63559322031.35582363620.17730496452.10605490791.06136363642.75442958050.35680715150.23872679050.95908156350.68506231186.514084507

0.15570519820.23378141441.62271805270.02216312060.46204265840.55454545451.12465964250.16881198570.02652519890.34940517930.09744631880.088028169

0.41787548910.86206896551.03555033630.28812056740.34384569920.25681818180.32437551790.09591590090.05305039790.10933767510.09989471880

0.00931569560.27030976040.61919504640.13297872340.18804061680.13409090910.11443905130.057549540600.05348038460.06120999930

10.163423917435.359438924623.45468132810.022163120617.1815397846.797727272728.686318614110.240940743211.909814323620.750389218411.229341625223.9436619718

Maybridge 75142,0000000

Maybridge Intermediate 13688,0000

MDPI 9367,0000

Menai 4512,0000

Nanosyn Explore 18613,0000

Nanosyn Pharma 44000,0000

NCI DTP 126705,0000

Otava 104258,0000

Peakdale 3770,0000

Pharmeks 84143,0000

Princeton 204215,0000

Ryan Intermediate 1136,0000

Druggable Rules

%

Rules4

15.93204309798.717280181129.614473400823.606978826720.15383285828.192312821420.677083333322.747217679241.531124925512.563704005722.2293024852

7.04731989065.627980376713.88470098369.841416563210.714285714311.85720332356.39583333339.784993418216.78446734222.84502089498.75447282

6.14719492016.818415726116.060018666110.92463676026.42770719910.51725237585.27083333339.666320954238.388827386511.4399653459.1564139013

1.60772790224.62451542083.20913202671.71870937922.80442485521.67392400950.82291666672.078263991410.21033807370.27774946491.6273712073

0.094572229514.84613537340.03589633140.11265490050.39538501430.001159628700.0149587139000.029410323

0.35633465062.91433668390.02153779880.10832201970.23766312330.1333572990.13541666670.0618293510.119219960800.2842997892

0.99638598984.36378606470.10768899420.2715271960.63736928530.10726565350.26041666670.3041605170.3150813250.00382224030.3823341993

3.85381835389.16154928135.4562423724.26066610826.63944343622.30592164391.63541666672.722485938813.23341565193.04377739271.7597176609

0.59276522441.32423067690.55998276980.41740084921.27257799670.63605633480.27083333330.74095496431.4136081070.10192640911.1470025979

2.60242510224.60393152422.13224208492.34264421274.22392187360.695197397801.08799712790.34914417100.2303808637

0.68564866421.53006964220.76100222560.27441578321.90562613430.55256306930.093750.54948342570.05960998040.03567424320.2401843047

0.12159286660.6586846890.26563285230.21664403940.44939936050.107265653500.33407794490.19586136420.16053409440.0735258076

0.04221974530.34649559160.15794385810.10543343250.04753262470.036528303600.11069448320.10218853790.00254816020.039213764

16.176917620825.944286253415.794385813818.026228371719.533748163511.68209939188.6562512.07966013817.542365664718.030781775614.464977207

Ryan Labo 59214

Sigma Aldrich 58298,0000000

Sigma Aldrich L 13929,0000

Sigma Aldrich R 69238,0000

Sigma Aldrich S 46284,0000

SPECS 172469,0000

Timtec MaxiVerse 9600,0000

Timtec Stock 100276,0000

Toslab 11743,0000

Tripos 78488,0000

World Molecules 20401,0000

Druggable Rules

%

Sheet1

Database ScoreACDAkosAkosAkosArrayAsinexDatabase ScoreACDAkosAkosAkosArrayAsinex

LithuaniaResyntheticOWHpPreformatedLithuaniaResyntheticOWHpPreformated

8765715614013446528600133672142408765715614013446528600133672.000000014240.0000

163910103189951111970310906812294172.966.170.768.981.593751986.3343

0.917323327813078049701768219070.917.818.920.615.611.905111012.0527

0.8537914451655411726652380.84.97.43.93.33.98108800.2135

0.79444563160230026710.70.82.00.80.70.13981990.0049

0.69594740955300.60.10.40.20.10.00134660.0000

0.55189916000.50.00.10.00.00.00000000.0000

0.412000000.40.00.00.00.00.00000000.0000

0.30000000.30.00.00.00.00.00000000.0000

0.20000000.20.00.00.00.00.00000000.0000

0.10000000.10.00.00.00.00.00000000.0000

96.494.996.388.797.621117498.6053

Asinex GoldAsinex PlatinumBionetChembridgeChembridgeChembridgeDatabase ScoreAsinex GoldAsinex PlatinumBionetChembridgeChembridgeChembridge

82699DVSExpressCNSDVSExpressCNS

1915763508030000321716191576.082699.035080.030000.0000000321716.0000

11440115941925574260322716991.075.271.872.986.773333384.4531

0.9354501684184043931447630.916.718.321.611.793000012.5224

0.8897457929063744010.83.75.62.10.09866671.0944

0.7228963418107280.70.80.50.40.00000000.1584

0.6636131401140.60.20.00.00.00000000.0213

0.517901090.50.00.00.00.00000000.0014

0.43600020.40.00.00.00.00000000.0002

0.3100000.30.00.00.00.00000000.0000

0.2000000.20.00.00.00.00000000.0000

0.1000000.10.00.00.00.00000000.0000

191576Total Score96.796.396.998.665000098.2512

ChemicalChemicalChemicalChemStarChemStarComgenexChemicalChemicalChemicalChemStarChemStarComgenex

DiversityDiversityDiversityPlatedDiversityDiversityDiversityPlated

CLabIDCAntiGCLabIDCAntiG

1755511104847254940000119247175551.0110484.072549.000000040000.0000119247.0000

0.11267037974355695155926000457771.072.272.277.771.067830065.000038.3884

0.9344472305314871445411138311480.917.718.818.717.930777825.060523.5085

0.812448532021840061989277420.85.73.92.44.41742823.978018.6115

0.717431707301041592114810.70.71.10.31.00442461.03606.7395

0.6188493232722530030.60.10.30.00.27043790.33751.5110

0.51912408552960.50.00.10.00.05858110.06500.0403

0.4339015300.40.00.00.00.00827030.00300.0000

0.30501100.30.00.00.00.00041350.00080.0000

0.20000000.20.00.00.00.00000000.00000.0000

0.10000000.10.00.00.00.00000000.00000.0000

96.396.299.194.758163495.480888.7991

Enamine RSEnamine SEvotecEvotecG & JIBS nEnamineEnamineEvotecEvotecG & JIBS n

Lead DiscoveryScreeningRSSLead DiscoveryScreening

76817

109695124420122998186718915109695.0124420.076817.0122998.00000001867.000018915.0000

1560598467621930428551492108531.051.168.128.534.842030079.914357.3777

0.93397729746275394026128651650.927.921.532.329.459747313.786824.5757

0.816611772417643268026012440.812.15.018.417.43247862.57105.2614

0.726481863824611392236830.71.71.07.56.48335750.86232.5276

0.63963531419167765870.60.20.21.10.81806210.19281.8620

0.5347401102880.50.00.00.00.00447160.00000.7613

0.4111000880.40.00.00.00.00000000.00000.1861

0.30000070.30.00.00.00.00000000.00000.0111

0.20000000.20.00.00.00.00000000.00000.0000

0.10000000.10.00.00.00.00000000.00000.0000

93.095.887.889.040147097.327392.5630

IBS SIFlabKeyOrganicsMaybridgeMaybridgeMDPIIBS SIFlabKeyOrganicsMaybridgeMaybridgeMDPI

IntermediateIntermediate

1721531094003473675142136881721531094003473675142.000000013688.0000

111729880819246284484482316104168.173.970.959.679007760.133065.1649

0.94010820302805010722493724120.921.016.720.912.842085732.461323.1750

0.812001700289812613714520.85.65.12.11.34252482.16833.8604

0.729501147178334852020.71.20.70.40.31114420.43471.5096

0.663710315117541450.60.20.10.00.09342310.23670.9288

0.5110261138250.50.00.00.00.00865030.02920.1334

0.428102250.40.00.00.00.00106470.00580.0214

0.314000010.30.00.00.00.00000000.00000.0032

0.27000000.20.00.00.00.00000000.00000.0000

0.10000000.10.00.00.00.00000000.00000.0000

96.196.594.274.277900595.469094.7966

MenaiNanosynNanosynNCIOtavaPeakdaleMenaiNanosynNanosynNCIOtavaPeakdale

ExplorePharmaDTPExplorePharmaDTP

45121861344000126705104258407745121861344000126705.0000000104258.00004077.0000

13510123913613877841663463279177.866.682.161.434828963.636480.4268

0.99074333602337368334916580.918.121.012.326.542914628.910914.5254

0.87912271399596134541300.81.45.32.53.76370312.65032.5509

0.7104103572982748100.70.21.50.61.64744880.50220.1717

0.661767416481350.60.10.60.10.78039540.07770.0000

0.50689562680.50.00.20.00.22177500.03260.0000

0.4070249120.40.00.00.00.07860780.00460.0000

0.30108520.30.00.00.00.02012550.00060.0000

0.2000920.20.00.00.00.00142060.00040.0000

0.1000000.10.00.00.00.00000000.00000.0000

97.595.197.794.491219895.815797.6748

PharmacophorePharmeksPrincetonRyan IntermediateRyan LaboSigmaPharmacophorePharmeksPrincetonRyan IntermediateRyan LaboSigma

1136AldrichAldrich

1000084143204215592145829810000841432042151136.000000059214.000058298.0000

19286495881469097544217829017192.958.971.966.373239471.229849.7736

0.9685225914215335112909212710.96.224.218.627.808098619.620532.8380

0.82986401176825282736810.80.28.24.61.76056343.81945.0513

0.7026752752693217700.70.02.20.90.36971831.10182.1253

0.60450557028815210.60.00.30.20.00000000.29181.5654

0.50155650667490.50.00.10.00.00000000.05570.6424

0.4034110132410.40.00.00.00.00000000.00880.1654

0.3010001480.30.00.00.00.00000000.00050.0247

0.20000000.20.00.00.00.00000000.00000.0000

0.10000000.10.00.00.00.00000000.00000.0000

99.394.096.296.311619796.128392.1860

SigmaSigmaSigmaSPECSSynthonesTalonSigmaSigmaSigmaSPECSSynthonesTalon

Aldrich LAldrich RAldrich SAldrich LAldrich RAldrich S

139296923846284172469280325169139296923846284172469.00000002803.000025169.0000

187534609430462122704232619615162.866.665.871.145539282.982577.9332

0.9341116539109043604645543950.922.021.521.218.809989014.609315.7158

0.812014564243110890227660.86.95.34.25.05134260.62792.4347

0.742114271596238702880.72.11.42.40.96881180.00000.8010

0.61035487364120600.60.40.51.00.14333010.00000.1430

0.53462137440310.50.10.00.10.01275590.00000.0616

0.4641720130.40.00.00.00.00046390.00000.0207

0.30011010.30.00.00.00.00017390.00000.0012

0.20000000.20.00.00.00.00000000.00000.0000

0.10000000.10.00.00.00.00000000.00000.0000

94.595.394.896.132406498.219897.1111

TimtecTimtecToslabTriposWorld MoleculesTimtecTimtecToslabTriposWorld Molecules

MaxiVerseStock20401MaxiVerseStock20401.0000

9600100276117437848896001002761174378488.0000000

178817258657776414614744182.172.449.281.727143072.2710

0.913542038226461914043640.912.718.320.321.947304019.2520

0.82815349230936958880.82.34.315.73.76618083.4822

0.77215079194823270.70.51.15.50.42987461.1220

0.611342894570.60.10.20.50.00305780.1676

0.517120170.50.00.00.00.00000000.0417

0.40361030.40.00.00.00.00000000.0059

0.3030010.30.00.00.00.00000000.0015

0.2000000.20.00.00.00.00000000.0000

0.1000000.10.00.00.00.00000000.0000

960097.796.391.1107.873560396.3438

PhysicoChemical Properties

Table 1

ACDAkosAkosAkosAsinexAsinexAsinex PlatinumBionetChembridgeChembridgeChemicalChemicalACDAkosAkosAkosAsinexAsinexAsinex PlatinumBionetChembridgeChembridgeChemicalChemicalACDAkosAkosAkosAsinexAsinexAsinex PlatinumBionetChembridgeChembridgeChemicalChemical

LithuaniaRe-syntheticOWHpPre-formatedGoldDVSExpressDiversity ClabDiversity IDCLithuaniaRe-syntheticOWHpPre-formatedGoldDVSExpressDiversity ClabDiversity IDCLithuaniaRe-syntheticOWHpPre-formatedGoldDVSExpressDiversity ClabDiversity IDC

87657156140134465286001424019157682699350803000032171617555111048487657.0000000156140.0000134465.000028600.000014240.0000191576.000082699.000035080.000030000.0000321716.0000175551.0000110484.000087657.000156140.000134465.00028600.00014240.000191576.00082699.00035080.00030000.000321716.000175551.000110484.000

logP >524148457732490359631164389861913883781646516065050324152logP >50.275482829.315418.520120.84978.174220.350123.141823.88265.486716.040928.768321.8602logP >50.6800.6990.6350.6390.3880.6820.0250.0660.0800.0020.0090.026

MW >5008313228661136324350151071480299519052270519398MW >5000.094835614.64458.45058.51400.00007.885617.89862.83640.00332.813715.40928.5062MW >5000.4580.5290.5020.4250.0000.4970.0100.0510.0090.0000.0020.014

MW 100.6670.3330.6670.5650.6670.6120.0000.0000.0000.0000.0000.000

HBdon >54787130281944441210683372HBdon >50.00053620.05570.09670.09790.13340.23180.00480.00290.00670.03290.04730.3367HBdon >50.4260.3390.3380.3690.4390.4660.0000.0000.0000.0000.0000.000

RotBond >15178179233244767954054692312718312247863654RotBond >150.02031785.07432.41252.68180.66712.11618.37130.36200.06000.97042.72633.3073RotBond >150.5060.5420.5090.5190.4210.5130.0030.0240.0010.0000.0010.002

cycles >6397849254200512853371110618884666cycles >60.00452900.54370.18890.69930.03510.67080.40750.03140.03330.19210.50360.6028cycles >60.0050.6100.5730.0080.5000.7090.0010.0010.0000.0000.0000.000

SingleChain>7369263992187617732590383767411158SingleChain>70.00420961.69010.68490.30420.04210.92550.03020.25660.12670.11690.42211.0481SingleChain>70.0000.0000.0000.0000.0000.0000.0010.0000.0010.0000.0000.000

ring size >79701038469781457811691735361597ring size >70.01106590.66480.34880.27270.09830.30170.00120.04560.30330.22850.20560.5403ring size >70.0110.0060.0030.0030.0010.0030.0000.0000.0000.0000.0000.000

halogene >725631922161015623020915269111359halogene >70.00292052.04430.16060.35310.03510.32520.00000.59580.05000.08360.06320.3249halogene >70.0050.0190.0030.0060.0010.0050.0000.0000.0020.0000.0000.000

CF3CF2CF21371198341272430276615146CF3CF2CF20.00156290.76730.02530.04200.04920.12680.00000.00570.02330.02050.00850.1321CF3CF2CF20.0020.0060.0010.0000.0000.0010.0000.0000.0000.0000.0000.000

Reactive897418151247492666522779391255433647290131229414801Reactive0.102376311.624818.40559.32170.035111.89034.730415.801012.15679.01827.003113.3965Reactive0.1020.1080.1020.0030.1840.1180.0140.0130.0530.0040.0050.006

N&O72832482186028044056N&O0.00007990.01790.02380.16780.01400.09710.00000.07980.00000.01370.00000.0507

SlogP>50.201s_logP>50.137s2_logP>50.682

Table 3Weight>5000.078s_MW>5000.039s_MW>5000.497

ChemStarChemStarComgenexEnamine RSEnamine SEvotecEvotecG & JIBS nIBS SIFlabKeyOrganicsChemStarChemStarComgenexEnamine RSEnamine SEvotecEvotecG & JIBS nIBS SIFlabKeyOrganicsWeight100.612

72549400001192471096951244207681712299818671958991721531094003473672549.000000040000.0000119247.0000109695.0000124420.000076817.0000122998.00001867.0000195899.0000172153.0000109400.000034736.0000a_don>50.002HBdon>50.001HBdon>50.466

logP >51718881857515439830318172732042765445320946940287728231logP >523.691574020.462563.023836.309825.572335.565034.768923.83501.638127.266426.299823.6959b_rotN>100.189RotBond_100.097RotBond_100.513

logP >6736537094674419872134281445222351151150120200100483762logP >610.15175959.272539.199318.115710.792518.813518.17188.08780.766211.73379.184610.8303

MW >5007039324646678329621542947723672552623912163815064986MW >5009.70240808.115039.144030.048812.400762.125654.67981.39261.220512.569113.76972.8386Unacceptable groups

Weight >6001292632477467392501147992149639172908324977Weight >6001.78086531.58004.00356.14342.010119.265317.47670.16070.46811.68922.96980.2217===================

MW 100.29221630.05250.00250.04100.15670.18360.06750.05360.38230.15510.06950.0086Single Chain>70.000Single Chain>70.000Single Chain>70.000

HBdon >525120404123421952796224771HBdon >50.34597310.51000.00000.00360.09890.54810.07720.10710.40630.13010.07040.0029nbrofringSize > 70.003nbrofringSize > 70.003nbrofringSize > 70.003

RotBond >15211611522447352032966195492787623204555143989124RotBond >152.91664942.880020.52294.74322.383925.448822.66381.23191.04393.20303.64630.3570CF3CF2CF20.001CF3CF2CF20.001CF3CF2CF20.001

cycles >64522843185431016212831110497190532510cycles >60.62302720.71000.26670.49500.81662.77022.52930.00000.25371.10660.29710.0288nbr_halogene0.005nbr_halogene_70.005nbr_halogene_70.005

SingleChain>76365176197644440457028334198649088SingleChain>70.87664891.29255.19680.58710.35360.05860.05691.49970.17051.15360.44790.2533no N & O0.001no N & O0.001no N & O0.001

ring size >724719508327607920560616815ring size >70.34045960.48750.00000.07570.22180.00000.00570.48210.10460.35200.15360.0432Reactive

halogene >72021349583283561194436757209halogene >70.27843250.33500.07970.07570.22750.07290.09670.21420.00200.21320.05210.60170.118Reactive0.118Reactive0.118

CF3CF2CF2625300830705178142CF3CF2CF20.08545950.13250.00000.00000.06670.00000.00570.00000.00260.10340.01280.0058

Reactive881945489059173091823989241343425555402348379875235Reactive12.155922211.37007.596815.779214.659211.617210.922113.65832.828013.64087.300715.0708

N&O8740770420600027933827N&O0.119919010.19250.00000.00360.16560.00000.00000.00000.01380.05400.03470.0777

Exotics110890012400024303281Exotics0.15162170.22250.00000.00000.09970.00000.00000.00000.01230.17600.02560.0029

Error Atom Type4123001857010124886727Error Atom Type0.05651350.05750.00000.00001.49250.00000.00080.00000.00610.28350.06120.0777

Table 5

MaybridgeMaybridgeMDPI 19367MenaiNanosynNanosynNCIOtavaPeakdalePharmeksPrincetonRyanMaybridgeMaybridgeMDPIMenaiNanosynNanosynNCIOtavaPeakdalePharmeksPrincetonRyan

IntermediateExplorePharmaDTPIntermediateIntermediateExplorePharmaDTPIntermediate

751421368845121861344000126705104258377084143204215113675142.000000013688.00009367.00004512.000018613.000044000.0000126705.0000104258.00003770.000084143.0000204215.00001136.0000

logP >51028213461687601429087481320017637541246165187954logP >513.68342609.833418.010013.320023.048419.881810.417916.916714.350129.255025.40414.7535

logP >639985758752212291338468766204182114352002315logP >65.32059304.20089.34134.898012.30867.69095.42685.95064.827613.59009.80491.3204

MW >500157825057390199520546408611820314976232801MW >5002.10002401.82646.11721.994710.71834.66825.05745.86815.384617.798311.39980.0880

Weight >60023775201108220303710157358632650Weight >6000.31540280.54792.14580.22164.41630.00002.39690.97350.18574.26181.59880.0000

MW 100.17566740.17531.08890.00000.46740.12271.51690.00860.00000.07960.18310.0880

HBdon >5123106287113129201201803421HBdon >50.16369010.07310.66190.17730.38150.29772.30460.11510.00000.21390.16750.0880

RotBond >1560411233015751591714618041024058687125RotBond >150.80381150.81823.52300.33244.03481.34325.63991.73032.70564.82273.36462.2007

cycles >658187511371391026319113307340cycles >60.07718720.13150.80070.02220.73600.31590.80980.30600.02651.58060.35940.0000

SingleChain>722387127839246734903729807139974SingleChain>70.29677140.63561.35580.17732.10611.06142.75440.35680.23870.95910.68516.5141

ring size >711732152186244142517612941991ring size >70.15570520.23381.62270.02220.46200.55451.12470.16880.02650.34940.09740.0880

halogene >73141189713641134111002922040halogene >70.41787550.86211.03560.28810.34380.25680.32440.09590.05310.10930.09990.0000

CF3CF2CF27375863559145600451250CF3CF2CF20.00931570.27030.61920.13300.18800.13410.11440.05750.00000.05350.06120.0000

Reactive76374840219713198299136347106774491746022932272Reactive10.163423935.359423.45470.022217.18156.797728.686310.240911.909820.750411.229323.9437

N&O211419369610114529917790119687N&O0.28080173.06113.93940.13300.05370.25914.182217.06340.02650.02260.03330.6162

Exotics317196021552062781932230Exotics0.04125520.51871.02490.00000.01070.03414.10880.26660.02650.11050.10920.0000

Error Atom Type2581226715560152815521111203Error Atom Type0.34334990.89130.71530.02220.29550.13641.20600.14870.05310.13190.05880.2641

Table 7

Ryan LaboSigmaSigmaSigmaSigmaSPECSTimtecTimtecToslabTriposWorld MoleculesRyan LaboSigmaSigmaSigmaSigmaSPECSTimtecTimtecToslabTriposWorld Molecules

AldrichAldrich LAldrich RAldrich SMaxiVerseStockAldrichAldrich LAldrich RAldrich SMaxiVerseStock

592145829813929692384628417246996001002761174378488204015921458298.000000013929.000069238.000046284.0000172469.00009600.0000100276.000011743.000078488.000020401.0000

logP >594345082412516345932848623198522810487798614535logP >515.98.717280229.614523.607020.153828.192320.677122.747241.531112.563722.2293

logP >641733281193468144959204506149812197122331786logP >67.05.627980413.88479.841410.714311.85726.39589.785016.78452.84508.7545

MW >50036403975223775642975181395069693450889791868MW >5006.16.818415716.060010.92466.427710.51735.27089.666338.388811.44009.1564

Weight >60095226964471190129828877920841199218332Weight >6001.64.62451543.20911.71872.80441.67390.82292.078310.21030.27771.6274

MW 100.42.91433670.02150.10830.23770.13340.13540.06180.11920.00000.2843

HBdon >55902544151882951852530537378HBdon >51.04.36378610.10770.27150.63740.10730.26040.30420.31510.00380.3823

RotBond >1522825341760295030733977157273015542389359RotBond >153.99.16154935.45624.26076.63942.30591.63542.722513.23343.04381.7597

cycles >63517727828958910972674316680234cycles >60.61.32423070.56000.41741.27260.63610.27080.74101.41360.10191.1470

SingleChain>7154126842971622195511990109141047SingleChain>72.64.60393152.13222.34264.22390.69520.00001.08800.34910.00000.2304

ring size >7406892106190882953955172849ring size >70.71.53006960.76100.27441.90560.55260.09380.54950.05960.03570.2402

halogene >7723843715020818503352312615halogene >70.10.65868470.26560.21660.44940.10730.00000.33410.19590.16050.0735

CF3CF2CF2252022273226301111228CF3CF2CF20.00.34649560.15790.10540.04750.03650.00000.11070.10220.00250.0392

Reactive957915125220012481904120148831121132060141522951Reactive16.225.944286315.794418.026219.533711.68218.656312.079717.542418.030814.4650

N&O18393268846027732465862030N&O0.315.99711830.63180.66445.99130.14260.05210.08580.01700.00000.1471

Exotics25778495719419007621328073Exotics0.413.46358370.40920.28024.10510.04410.02080.13160.06810.00000.3578

Error Atom Type1484751316230012302151981923Error Atom Type0.20.81477920.09330.23400.64820.07130.00000.21440.16181.04350.1127

44000126705.000104258.0003770.00084143.000204215.0001136.00059214.00058298.00013929.00069238.00046284.000172469.000

8765715614013446528600142401915768269935080300003217161755511104847254940000119247109695124420.000000076817.0000122998.00001867.0000195899.0000172153.0000109400.000034736.000075142.000013688.00009367.00004512.0000186139600100276117437848820401

2889819

Sheet2

Sheet3

FiltrageGroupes Ractifs

sulfonyl halides

acyl halides

alkyl halides

anhydrides

halopyrimides

-halocarbonyl

1,2-dicarbonyl

aldehydes

Aliphatic ketones

Perhalo ketones

Aliphatic esters

Thio esters

Phosphonate esters

aziridines

Epoxides

imines

Michael acceptors

X = F, Cl, Br, I, tosyl, methyl

R = alkyl, aryl, hetroalkyl, heteroaryl

These reactive functional groups are generally prone to decomposition under hydrolytic conditions. They are reactive toward protein and biological nucleophiles (glutathione, dithiothreitol) and they exhibit poor stability in serum. (Reactive compounds and in vitro false positives in HTS, DDT, 2, 9, 382 (1997))

Tudor I. Oprea, Comp. Aided. Mol. Des. 14, 251-264 (2000)

% de molcules < 2 violation des critres

Chart1

92.660024642985.144023895388.021383285593.209735870496.802282333499.8797.947855949498.706002235494.34678077788.961767196764.508958816587.290006637667.575080871664.398504257295.232992172290.282239913992.416818618894.043642044196.449913024996.752002716197.761528015186.294162750289.360322952395.393045425496.3199.71000051592.579881668192.826845169192.045526504595.395132064892.954784393371.719320297295.21305465762.882394790639.4493.6343479156

ACD

Akos

Aldrich

Asinex

Bionet

ChembridgeDVS

ChembridgeEx

ChembridgeHTS

ChemDiv

ChemStar

Comgenex

Enamine

Evotec

EvotecLeadDis

G&J

IBS

Iflab

KeyOrganics

Maybridge

MaybridgeHTS

Menai

NCI-aug2D

NCI-DTP

Otava

Peakdale

Pharmacophore

Princeton

Ryan

SPECS

TalonHTS

Timtec

Toslab

Tripos

WDI

WDI antibiotics

WorldMolecules

fournisseur

Pourcentage

Sheet1

Sheet1

92.660024642985.144023895388.021383285593.209735870496.802282333499.8797.947855949498.706002235494.34678077788.961767196764.508958816587.290006637667.575080871664.398504257295.232992172290.282239913992.416818618894.043642044196.449913024996.752002716197.761528015186.294162750289.360322952395.393045425496.3199.71000051592.579881668192.826845169192.045526504595.395132064892.954784393371.719320297295.21305465762.882394790639.4493.6343479156

ACD

Akos

Aldrich

Asinex

Bionet

ChembridgeDVS

ChembridgeEx

ChembridgeHTS

ChemDiv

ChemStar

Comgenex

Enamine

Evotec

EvotecLeadDis

G&J

IBS

Iflab

KeyOrganics

Maybridge

MaybridgeHTS

Menai

NCI-aug2D

NCI-DTP

Otava

Peakdale

Pharmacophore

Princeton

Ryan

SPECS

TalonHTS

Timtec

Toslab

Tripos

WDI

WDI antibiotics

WorldMolecules

supplier

Percentage

0 and 1 Flag

Sheet2

Sheet3

Criblage virtuel de cibles potentielles (virtual High Throughput Screening) vHTSStructure 3D cibleSite Fonction de la protineLigand ComplexChimiothquesModle pharmacophoreAlgorithmes, OrdinateursCriblage vHTSListe de touches (hits)

ApplicationCriblage Virtuel sur SARS-CoV Mpro

Donnes du WHO sur le SARSau 31 dcembre 2003 http://www.who.int/csr/sars/country/table2004_04_21/en/index.html

29 pays touchs 8096 cas 774 morts Canada 251 cas 43 morts

Transmission par contact face- face

Projet SRAS: Nos CollaborateursS. Sirois, et al., Virtual Screening for SARS-CoV Protease Based on KZ7088 Pharmacophore Points, J. Chem. Inf. Comput. Sci. 44, 1111-1122, (2003).Q-S. .Du, et al. , Polyprotein Cleavage Mechanism of SARS-CoV MPro and Chemical Modification of the Octapeptide, Peptides 25, 1857-1864 (2004).Dongqing Wei, et al. , Anti-SARS Drug Screening by Molecular Docking, Amino Acids, accepted (2005)Q-S. .Du, et al. , Molecular Modelling and Chemical Modification for Finding Peptide Inhibitor Against SARS-CoV Mpro, Analytical Biochemistry, 337, 262-270 (2005).

Tianjin Institute of Bioinformatics and Drug Discovery (TIBDD) et Tianjin Normal University

Modlisation 3D par HomologieSi la structure 3D de la cible est inconnueConstruire la serrure pour ensuite trouver la cl

Modlisation par Homologie Structure 3D - SARS-CoV Mpro HCov 40%, TGEV 44%304 AA. domaine 1 (res. 899) mauvedomaine 2 (res. 100183) jaunedomaine 3 (res. 200300) bleuBoucle (res. 184199 ) liant les domaines 2 et 3 mauve . Site de liaison localis entre les domaines 1-2K. Anand, et al. Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs. Science 300, 1763-1737 (2003)

Modlisation et Superposition des Structures 3DModlisation 3D de SARS MPro partir de HCoVPDB: 1P9S

ExprimentalePDB: 1UJ1

RMS = 1.4

PeptidomimtiqueDyade Catalytique de SARS-CoV Mpro His-41 et Cys-145

Superposition des ligands naturelsSuperposition des peptides 1UK4-SARS (vert) et 1P9U-TGEV (rouge) partir des coordonnes des structures cristallines Modes de liaisons diffrents pour les ligands du SARS et TGEV MPro

Superposition des ligands naturelsDomaines I et IISuperposition de 6 structures complexes du SARS: 1UK4, 1WOF, 2A5I, 2AMD, 2AMQ, 2D2D Montre une poche de liaison conserve o le sous-site S1 est dans un creux prononc qui contient les rsidus de la diades catalytiques Cys145 and His41.

Superposition des ligands naturelsSurface molculaire de la poche partir des 6 ligands complexs 1UK4, 1WOF, 2A5I, 2AMD, 2AMQ, 2D2D. Bleu: rgion hydrophobe Vert hydrophileRouge: surface expose au solvent

Superposition des ligands naturelsSurface molculaire consensus partir des 6 ligands complexs 1UK4, 1WOF, 2A5I, 2AMD, 2AMQ, 2D2D. Pair dlectrons libre: pourprehydrophobe: vert

Enthalpie, entropie

Comment trouver dautres types dinhibiteurs

Modle Pharmacophore de KZ7088 KZ7088 amarr dans site de liaison de SARS-CoV Mpro

7 points pharmacophores

Criblage Virtuel sur 5M molcules a donn 2789 touches (hits)0.07% satisfait 5 des 6 liaisons hydrognes (points pharmacophore)

Proprits physico- chimiques%Violation17023 117 2 47 >2S. Sirois, et al., Virtual Screening for SARS-CoV Protease Based on KZ7088 Pharmacophore Points, J. Chem. Inf. Comput. Sci. 44, 1111-1122, (2003).

Exemples de touches obtenuesFonction dvaluation

Modification virtuelle Modification

Calcul E int

Convergence?

Principales Cibles anti-VIH-1

gp120/gp41 :CCR5/CXCR4

Modles thoriques: CCR5Superposition de 3 modles CCR5 1OPN, 1OPW et 1OPT

Structure 3D: gp120 (1G9M)

Complexe CCR5 gp120 incluant boucle V3

Servir la conception rationnelle de nouveau inhibiteurs base sur interactions entre le co-receptor CCR5 et la boucle V3.

HIV-1 V3 Loop for Structure-Based Drug Design S. Sirois, T. Sing and K.C.-Chou,Current Protein and Peptide Science, 6(5), 413-422 (2005)

Structure of a V3-Containing HIV-1Gp120 core Huang et al. Science 11 Nov 2005

Superposition des Boucles V3 (RMN)

Structure 3D boucle V3 (RMN)GPG Position 25 Arg + bleuGln - rougePosition 10 Lys + bleu

Improving HIV-treatment: Predicting HIV coreceptor CCR5 and CXCR4 usage through V3 genotype

Modlisation par homologie des structures 3D de la boucle V3Corrlation avec lusage du corcepteur Choix de traitement R5 R5X4 X4Suite du projet

Virus Influenza H5N1Genetic Insight of The H5N1 Influenza Virus High Pathogenicity, Wei et al. soumis Nature Genetics novembre 2005356 gnes HA de H5N1

Criblage virtuel pour H5N1

Projet denvergureScreensaver Lifesaver ProjectComputational Drug Design at the University of OxfordThe National Foundation for Cancer Research Centre United Devices members

Virtual screening using grid computing: the screensaver project W. Graham Richards Nature Reviews Drug Discovery 1, 551-555 [2002].

Le Projet THINKhttp://www.chem.ox.ac.uk/curecancer.html3.5 milliard molcules cribles3.5 millions provenant de chimiothques connues respectant les critres de Lipinski dagents thrapeutiques Chaque molcule est varie 100 fois en ajoutant un substituant alatoirementChimie combinatoire3 semaines pour processer une cible

Combien dannes?Si 25000 cibles potentielles X 3 semaines= 75000/52 = 1442 annes pour 3.5 milliard molcules cribles

Si 1024-40 milliard molcules potentielles Avec une chimiothque de 3.5 milliard molcules On a cribl uniquement 109/10 24 soit 10-15 de toutes les molcules potentielles

Nombre de structures dans PDB

Solution: Calculs sur Rseaux dOrdinateurs (Grid Computing)

Construction de Chimiothques DiversifiesBut: Augmenter la qualitdu criblage en fonction diversit molculaire Proprits ADMET

Processus

Soit une chimiothque relleNombre de Violation0: mauve1 : bleu2: vertn: orange- rougeEnlve les composs non-ADMET

Comment la diversit est-elle dfinie?Comment reprsenter plus de 4 descripteurs?

Une combinaison de tous?

Topologique

2-D formules structuraleslectrostatiqueCharge positive ou ngativeGomtrique3-D forme et structureQuantiqueOrbitales atomiques et molculaires

Types de Descripteurs Molculaires

Exemple avec 25 Descripteurs25 descripteurs DLI (Drug-like Index)Chaque structrure est reprsente par un point dans un espace 25 dimensions

Reprsentation Graphiques 3D:

Soit 2 Chimiothques

Chimiothque assemblee

Nombre de molcules

Hole-Filler

25 DLI

Difference

Assemble (MCT)

125 170

100 706

24 674

MCT

100706

98 214

1492

Chimiothque-2

10 000

9247

753

O se situe le domaine des molcules biodisponibles?

Rsum Mthodes in silico et CHP

`> 10,000,000 composs sont cribls pour trouver une seule drogue1 drogue>1,000 hits6 drogues candidates10-15 ans$300 to >$800 milliontudes pr-cliniques tudes cliniques: Phase I III12 leadsProcessus de dcouverte de mdicaments: temps et cots

Vers la Bio-intelligence

MerciA tous les collaborateursDQ Wei, KC ChouT Sing, R HarriganR. RoyetV. Makarenkov

HCoV 229E ou 3C-like proteinase (3CLpro) Approcher la structure 3D partir de la comparaison de la squence avec les banques de donesRecherche d' homologiesSi la protine tudie partage plus de 30% d'acides amins, aprs alignement , avec une protine connue, on peut supposer que ces deux squences possdent des structures 3D proches

This is primarily achieved by the 33.1-kD HCoV 229E main proteinase (Mpro) (7), which is frequently also called 3C-like proteinase (3CLpro) to indicate a similarity of its cleavage-site specificity to that observed for picornavirus 3C proteinases [3Cpro (table S1)], although we have recently shown that the structural similarities between the two families of proteinases are limited (8). The Mpro (3CLpro) cleaves the polyprotein at no less than 11 conserved sites involving Leu-Gln (Ser,Ala,Gly) sequences (the cleavage site is indicated by ), a process initiated by the enzyme's own autolytic cleavage from pp1a and pp1ab (9, 10). This cleavage pattern appears to be conserved in the Mpro from SARS coronavirus (SARS-CoV), as we deduced from the genomic sequence published recently (11, 12) and prove experimentally here for one cleavage site (see below). The SARS-CoV polyproteins have three noncanonical Mpro cleavage sites with Phe, Met, or Val in the P2 position, but the same cleavage sites are unusual in other coronaviruses as well. The functional importance of Mpro in the viral life cycle makes this proteinase an attractive target for the development of drugs directed against SARS and other coronavirus infections.

The reason to select the octapeptide AVLQSGFR is as follows. (1) The protease-susceptible sites in proteins usually extend to an octapeptide, as generally formulated by P4P3P2P1P1P2P3P4 with the scissile bond located between the subsites P1 and P1, as generally expressed by P1P1 [2, 3 and 4]. (2) The SARS coronavirus enzyme and several viral proteinases exhibit Gln(Ser, Ala, and Gly) specificity [1]. (3) According to the "lock-and-key" mechanism in enzymology, the octapeptide cleavable by the SARS proteinase must have a good fit for binding to the active site. However, such a peptide, after a modification of its scissile bond with some simple routine procedure, will completely lose its cleavability but it can still bind to the active site. Actually, the molecule thus modified can be compared to a "distorted key" that can be inserted into a lock but can neither open the lock nor be pulled out from it, spontaneously becoming an ideal competitive inhibitor against the SARS proteinase. Therefore, it would provide us with useful insights for drug design by studying the binding mechanism of SARS proteinase with octapeptides that are cleavable by the enzyme itself. For a detailed discussion about the rationale of "distorted key," see a review by Chou [5] and Fig. 2 therein.