Drug Design Process

Discovery Phase

Tripos Software 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

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Molecular Modelling & Visualisation

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SYBYL/BaseMOLCADAdvanced ComputationAMPACMM2 & MM3Confort

MOLCADM

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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

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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

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Biomolecular Software

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BioPolymerComposerGeneFoldMatchMakerProTableSiteIDLeapFrog

Biopolymer Structure building

– proteins, DNA, RNA, Carbohydrates Structure editing

– conformations• alpha-helices, beta-sheets

– sequence• mutation, deletion, insertion, disulphide bonds, cyclisation

Sequence alignment Structural alignment Loop searching Secondary structure

– prediction and assignment

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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

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ProTableB

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analyses protein structure

• homology models or experimental (X-ray, NMR)

• uses molecular spreadsheet interactively with graphics

ProTable view

Compute structurequality data in MSS

And visualise it onthe actual structure

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SiteId– determines where on a protein a ligand may bind

• using 2 methods 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

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Dihydrofolate Reductase - anti cancer targetDihydrofolate Reductase - with backbone ribbonDihydrofolate Reductase backbone ribbonDihydrofolate Reductase - cavity detectedDihydrofolate Reductase - with MTX ligand

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Structure Activity Relationships (QSAR) and ADME

QSAR with CoMFA, Advanced CoMFA, HQSAR, clogP/CMR, Distill, VolSurfQ

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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

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QSAR - 3D QSAR - CoMFA

Comparative Molecular Field Analysis Descriptors are field strengths around

molecules - electrostatic, steric, H-bond ..

pKi = B(D1)+ C(D2)+ + ...A

PLS

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CoMFA - Interpretation High Coefficient (important) lattice points can

be plotted around molecular stuctures

Less steric bulk

More negative charge

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*courtesy MDL

VolSurf Just regular QSAR

– but uses specialised (ADME relevant descriptors) descriptors with PLS or PCA

What are the descriptors?– 72 descriptors - 5 classes

• Size & Shape• Hydrophilic regions• Hydrophobic regions• INTEraction enerGY (intergy moments)• Mixed descriptors

Predefined models– CACO2 permeability (A,D), skin permeability (A), Blood-Brain

barrier (D), LogP

A = Absorption, D=distribution

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Pharmacophore Perception

DISCOtech, GASP, Receptor

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DISCOtech 3D database queries

– and molecular alignmentsH-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

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Distance query - pharmacophorespecified by interfeature distances D1, D2, ...

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Hit molecule from LeadScreen

How does DISCOtech work?

MolecularStructures

Low EConformations

PharmacophoreModel

Conformergeneration

Cliquedetection

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Chemical Informatics

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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

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Unity example - similarity searching

Return all compounds in LeadScreen (50,000 compounds) at least 75% similar to

Search Takes 7 seconds and returns 8 compounds

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Unity - flexible 3D searching 3D searching

– return molecules which can present a specific arrangement of functionality (as defined in query)

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

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Concord

– Generates 3D molecular structures from 2D input

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StereoPlex

• Creates 3D structures of all structurally feasible stereoisomers

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FlexX CScore CombiFlexX FleS

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FlexX

– docks molecules into protein binding sites

– generates docked conformations

– generates docking scores

– assess complementarity between receptor & ligand

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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

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Database Screen with FlexX

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FlexX Virtual Screening Results

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FlexX docking & scoring.2873 compounds with 68 known actives

- PGRD data

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SGI™ Origin® 3800

64 64 CPUsCPUsVisualization

Data Array

SupercomputerSupercomputerss

Workstations

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Database

Screen with DOCK

Top 1%~10%

Virtual Screen Methods

Screen with FlexX

Lead Compounds

>2 Million Comps

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Molecular Diversity & Combinatorial Chemistry

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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

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Legion Combine reagents mode

R1 R2

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R4+15 diketones 31 hydrazines 465 products

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Selector

– filters compounds

– calculates descriptors - valid ones

– compares databases for similar molecules

– diversity selection - using a variety of distance methods

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Selector - Filtering

Filter the database

Excluded/includedcompounds

Filtering criteria

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Selector - Diversity Selection Distance based

– must use distance based with high-dimensional metrics– example is 2D but reality is 1000D

e.g. Dissimilarity selection

CompoundSelect compound at randomPick most different compound from 1stPick most different compound from selected

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DiverseSolutions - Diversity Selection

Cell based– divide space into cells - pick a compound form

each

Compound

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BCUT1

BCUT2