In silico drug discovery, which is basically the design or discovery of small molecules that are complementary in shape and charge to the bio-molecular target.
Having this technology allows us to know in advance how molecules will interact in an active site of a macromolecule
Drug discovery strategy final draft
Drug DiscoveryAnaeli ShockeyDelaine M. Zayas-BazánNicollle A. RosaZuleika VelázquezStudent Mentor: Mr. Carlos Castroda
Introduction• Food and Drug Administration (FDA)– Drug Discovery and Development– Clinical Trials– FDA Reviews and New Drug Application (NDA)– Manufacturing• Considered Parameters– Absorption– Distribution– Metabolism– Excretion• What is In silico drug discovery?
.Pharmacophoreidentification andPharmacophore ModelGeneration (LigandScout)Identification of Top-hitsand potential LeadCompounds.(Ranking of bindingenergies)Drug Discovery StrategyPrimary SequenceAnalysis; degreeconservation(NCBI/Swiss-Prot)Biological Problem(Biomedically Relevant Condition or Process)Identification of optimaltarget (s)for drug developmentIdentification of compounds that fulfillrequirements of Pharmacophore modelFiltering SmallchemicalcompoundsDatabasesTarget AnalysisNumber, qualityand distance of“hot spots’3D Structurewww.pdb.orgPyMolBioAssaySecondary Screening(AutoDock Vina)Primary Screening:Pharmacophore Model(ZINCPharmer)High AffinityLeadCompoundsFurther refinement ofPharmacophore ModelFTMap andIn Silicoscreening ofchemical probesTherapeuticallyrelevant proteintargetsDocking/screening ofFiltered DatabasesBCDA
Identification of Top-hitsand potential LeadCompounds.(Ranking of bindingenergies)Drug Discovery StrategyIdentification of compounds that fulfillrequirements of Pharmacophore modelBioAssaySecondary Screening(AutoDock Vina)High AffinityLeadCompoundsFurther refinementof PharmacophoreModelDocking/screening ofFiltered DatabasesDWork Plan
Work Plan• Run the Docking/Screening (“AutoDock Vina”)– This is needed for the analysis of the top hits– It is achieved by the utilization of the program Auto Dock• Download Results and Ranking of Top Hits– For this, the programs CyberDuck and Excel were used.– The results were downloaded and then opened with Excel tosort by affinity– Select the drugs with the highest affinity– Look for information about the drugs and take the pictures
Work Plan• Analyze Interactions–Open Autodock and let the program analyzethe results–Take pictures of the interactions
Name AffinityZINC06716957 -11.4ZINC14880002 -11.4ZINC22940637 -10.6CID_64143_Nelfinavir -10.5Zinc14879987_Tipranavir -10.5ZINC02570819 -10.4ZINC00896717 -10.4ZINC03951740 -10.4zinc_3951740_lopinavir -10.4ZINC22448696 -10.2DMP -10ZINC03914169 -10ZINC52955754 -10Identification of Top-hitsSteps One and Two
Lopinavir• zinc_3951740_lopinavir -10.4• Antiretroviral of the protease inhibitor class• Used with ritonavir (protease inhibitor)• Oral ingestion
Ergoloid• ZINC00896717 -10.4• Mixture of methanesulfonate salts• Used to treat dementia and age-related cognitiveimpairments• Also used in a patients recovery after stroke• Oral ingestion and parenteral
Zafirlukast• ZINC14880002 -11.4• Oral ingestion• Leukotriene receptor antagonist• Inhibits what causes inflammation in respiratorysystem
Images of the Drug’s Interactions with the aminoacids of the Proteases of HIV
Images of the Drug’s Interactions with theamino acids of the Proteases of HIV• Due to technical difficulties with the program, theimages of the other three drugs’ interactions with theamino acids of the proteases could not be presented.• This images composed the last step: the analysis of theresults.
Conclusion• The fourteen drugs with the highest affinity werechosen.• These range from -10 to -11.4• Nilotinib, Lopinavir, Ergoloid, and Zafirlukastwere evaluated using AutoDock Vina, CyberDuckand Excel.• The drugs with the highest affinity to the HIVrelated protein are Zafirlukast and Nilotinib.