Drug Design Process Discovery Phase

Tripos Software n SYBYL & its modules SYBYL, Concord, MOLCAD, SiteId, Advanced Computation, GASP, DISCOtech, HQSAR, QSAR, AMPAC, Advanced CoMFA, Distill, clogP/cMR, Biopolymer, Composer, GeneFold, ProTable, MatchMaker, Leapfrog, HiVol, CombiLibMaker/Legion, CLM 3D option, DYANA, Dynamics, Selector, Triad, Mardigras, FlexS, CScore, Confort, Stereoplex, DiverseSolutions, Receptor, MM2/3, VolSurf, FlexX, CombiFlexX, Unity Base, Unity 3D

SYBYL Graphics window Text port Software Introduction

Molecular Modelling & Visualisation Modelling & Visualisation SYBYL/Base MOLCAD Advanced Computation AMPAC MM2 & MM3 Confort

MOLCAD Modelling & Visualisation

Advanced Computation –creates molecular conformations using a variety of methods allows user defined constraints or constraints defined from other molecules with all SYBYL force fields for energy calculations Modelling & Visualisation

MM3 & AMPAC –generating high quality molecular structures AMPAC - very high quality (semi- emprirical calculations) MM3 - high quality (advanced molecular mechanics calculations) –generation high quality structral data MM3 heats of formation, vibrational spectra Modelling & Visualisation

Biomolecular Software BioPolymer Composer GeneFold MatchMaker ProTable SiteID LeapFrog

Biopolymer n Structure building –proteins, DNA, RNA, Carbohydrates n Structure editing –conformations alpha-helices, beta-sheets –sequence mutation, deletion, insertion, disulphide bonds, cyclisation n Sequence alignment n Structural alignment n Loop searching n Secondary structure –prediction and assignment Biomolecular Software

Composer –builds protein structure from sequence using homology modelling to model proteins of unknown structure based on known protein structures when >30% sequence identity exists with known structure Biomolecular Software

ProTable Biomolecular Software n analyses protein structure homology models or experimental (X-ray, NMR) uses molecular spreadsheet interactively with graphics

ProTable view Compute structure quality data in MSS And visualise it on the actual structure Biomolecular Software

SiteId –determines where on a protein a ligand may bind using 2 methods n Grid method –automated determination of cavities –places protein in grid –determines which grid points are deep within protein –clusters these points and presents them to user Biomolecular Software

Dihydrofolate Reductase - anti cancer targetDihydrofolate Reductase - with backbone ribbon Dihydrofolate Reductase backbone ribbon Dihydrofolate Reductase - cavity detectedDihydrofolate Reductase - with MTX ligand Modelling & Visualisation

Structure Activity Relationships (QSAR) and ADME QSAR with CoMFA, Advanced CoMFA, HQSAR, clogP/CMR, Distill, VolSurf QSAR & ADME

QSAR with CoMFA –computes specialised descriptors CoMFA, CoMSIA….. –determine structural factors responsible for molecular properties –generate models to predict biological activity or other molecular properties –visualise QSAR models QSAR & ADME

QSAR - 3D QSAR - CoMFA n Comparative Molecular Field Analysis n Descriptors are field strengths around molecules - electrostatic, steric, H- bond.. pKi = B(D 1 ) + C(D 2 ) A PLS QSAR & ADME

CoMFA - Interpretation n High Coefficient (important) lattice points can be plotted around molecular stuctures Less steric bulk More negative charge QSAR & ADME

*courtesy MDL

VolSurf n Just regular QSAR –but uses specialised (ADME relevant descriptors) descriptors with PLS or PCA n What are the descriptors? –72 descriptors - 5 classes Size & Shape Hydrophilic regions Hydrophobic regions INTEraction enerGY (intergy moments) Mixed descriptors n Predefined models –CACO2 permeability (A,D), skin permeability (A), Blood-Brain barrier (D), LogP A = Absorption, D=distribution QSAR & ADME

Pharmacophore Perception DISCOtech, GASP, Receptor Pharmacophore perception

DISCOtech n 3D database queries –and molecular alignments H-bond Donor H-bond Acceptor Hydrophobe H-bond Donor H-bond Acceptor Hydrophobe x1,y1,z1 x2,y2,z2 x3,y3,z3 x4,y4,z4 x5,y5,z5 Spatial query - pharmacophore points specified by x,y,z D1 D2 D3 D4 Distance query - pharmacophore specified by interfeature distances D1, D2,... Pharmacophore perception Hit molecule from LeadScreen

How does DISCOtech work? Molecular Structures Low E Conformations Pharmacophore Model Conformer generation Clique detection Pharmacophore perception

Chemical Informatics  UNITY  CONCORD  SteroPlex  ChemEnlighten  AUSPYX  HiVol/HiStats  Molconn-Z

Unity –Searches databases of chemical structures to return molecules matching the query 2D substructure searching similarity searching - those fingerprints again 3D searching, verify, rigid, fully flexible Chemical Informatics

Unity example - similarity searching n Return all compounds in LeadScreen (50,000 compounds) at least 75% similar to Search Takes 7 seconds and returns 8 compounds Chemical Informatics

Unity - flexible 3D searching n 3D searching –return molecules which can present a specific arrangement of functionality (as defined in query) n 2 ways to do this –rigid 3D search of multiple conformations generate many conformations for all mols in database do rigid searching on all conformations of all molecules –fully flexible searching (Tweak algorithm) store 1 conformation per molecule in the database flex it on the fly to match the 3D query slower than rigid searching but more valid hits Chemical Informatics

Concord –Generates 3D molecular structures from 2D input Chemical Informatics StereoPlex Creates 3D structures of all structurally feasible stereoisomers

Virtual Screening  FlexX  CScore  CombiFlexX  FleS

Virtual Screening

FlexX –docks molecules into protein binding sites –generates docked conformations –generates docking scores –assess complementarity between receptor & ligand Virtual Screening

CScore –calculates scores for ligands in protein binding site using a number of different functions G_score D_score PMF_score FlexX –computes the consensus between different scoring functions Virtual Screening

Database Screen with FlexX Virtual Screen Virtual Screening

FlexX Virtual Screening Results % actives found % compounds screened FlexX docking & scoring compounds with 68 known actives - PGRD data Virtual Screening

SGI™ Origin® CPUs Visualization Data Array Supercomputers Workstations Virtual Screening

Database Screen with DOCK Top 1%~10% Virtual Screen Methods Screen with FlexX Lead Compounds >2 Million Comps Virtual Screening

Molecular Diversity & Combinatorial Chemistry Diversity and CombiChem  Legion  CombiLibMaker  DiverseSolutions  Selector

Legion/CombiLibMaker –builds virtual combinatorial libraries –have 2 modes of operation core + sidechains combine reagents – provide output for DiverseSolutions - lib design Diversity and CombiChem

Legion n Combine reagents mode + 15 diketones 31 hydrazines 465 products Diversity and CombiChem

Selector –filters compounds –calculates descriptors - valid ones –compares databases for similar molecules –diversity selection - using a variety of distance methods Diversity and CombiChem

Selector - Filtering Filter the database Excluded/included compounds Filtering criteria Diversity and CombiChem

Selector - Diversity Selection n Distance based –must use distance based with high-dimensional metrics –example is 2D but reality is 1000D n e.g. Dissimilarity selection Compound Select compound at random Pick most different compound from 1st Pick most different compound from selected Diversity and CombiChem

DiverseSolutions - Diversity Selection n Cell based –divide space into cells - pick a compound form each Compound Diversity and CombiChem BCUT1 BCUT2