Drug Design Process: Discovery Phase

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
Software Introduction SYBYL
Graphics
window
Text
port
Molecular Modelling &
Modelling & Visualisation
Visualisation
SYBYL/Base
MOLCAD
Advanced Computation
AMPAC
MM2 & MM3
Confort
MOLCAD
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
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
Biomolecular Software
BioPolymer
Composer
GeneFold
MatchMaker
ProTable
SiteID
LeapFrog
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
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
ProTable
 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
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
Dihydrofolate
Dihydrofolate
Dihydrofolate
DihydrofolateReductase
Reductase
Reductase
Reductase --backbone
-anti
- with withcancer
backbone
cavity
MTX target
ribbon
ribbon
detected
ligand
Structure Activity Relationships
QSAR & ADME
(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 - 3D QSAR - CoMFA
 Comparative Molecular Field Analysis
QSAR & ADME
 Descriptors are field strengths around

molecules - electrostatic, steric, H-bond ..
PLS
pKi = A + B(D1) + C(D2) + ...

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

*courtesy MDL
VolSurf
 Just regular QSAR
– but uses specialised (ADME relevant descriptors) descriptors with
PLS or PCA
QSAR & ADME
 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
Pharmacophore perception
Pharmacophore Perception
DISCOtech, GASP, Receptor
DISCOtech
 3D database queries
– and molecular alignments
H-bond Donor
Hydrophobe
H-bond Acceptor
x1,y1,z1 D2 x4,y4,z4
x3,y3,z3 H-bond Donor

D1
D3 D4 x5,y5,z5 Hydrophobe
x2,y2,z2
H-bond Acceptor
Distance query - pharmacophore
Hitquery
Spatial molecule
specified from distances
by -interfeature LeadScreen
pharmacophore points specified
D1, D2, ... by x,y,z
How does DISCOtech work?
Low E
Conformations
Molecular Pharmacophore
Structures Model
Conformer Clique
generation detection
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
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

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
Concord
– Generates 3D molecular structures from 2D

input
StereoPlex
• Creates 3D structures of all structurally feasible
stereoisomers
Virtual Screening
Virtual Screening
 FlexX
 CScore
 CombiFlexX
 FleS
Virtual Screening
FlexX
Virtual Screening
– docks molecules into protein binding

sites
– generates docked conformations
– generates docking scores
– assess complementarity between
receptor & ligand
CScore
– calculates scores for ligands in
Virtual Screening
protein binding site

• using a number of different
functions
G_score D_score PMF_score
FlexX
– computes the consensus between
different scoring functions
Virtual Screen
Virtual Screening
Screen with FlexX

Database
FlexX Virtual Screening Results
Virtual Screening
100
90
80
70
60
% actives
50
40
found
30
20
10
0 10 20 30 40 50 60 70 80 90 100
% compounds screened
FlexX docking & scoring.

2873 compounds with 68 known actives
- PGRD data
Virtual Screening Visualization 64 CPUs
SGI™ Origin® 3800

Supercomputers
Data Array Workstations

Virtual Screen Methods
Virtual Screening
Screen with DOCK

Top 1%~10%
Database
Screen with FlexX
>2 Million Comps

Lead Compounds
Molecular Diversity &
Diversity and CombiChem
Combinatorial Chemistry
 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
Legion
 Combine reagents mode
R3
O O
+
N N R2
R1
R1 R2 R4
N N
R3
R4
15 diketones 31 hydrazines 465 products

Selector
– filters compounds
– calculates descriptors - valid ones
– compares databases for similar
molecules
– diversity selection - using a variety of
distance methods
Selector - Filtering
Filter the database

Excluded/included
compounds
Filtering criteria
Selector - Diversity Selection
 Distance based
– must use distance based with high-dimensional metrics
– example is 2D but reality is 1000D
 e.g. Dissimilarity selection
Pick
Pick most
most
Select different
different
compound compound
compound from
from
at random 1st
selected Compound
DiverseSolutions - Diversity
Selection
 Cell based
– divide space into cells - pick a compound form each
BCUT1
BCUT2
Compound

Drug Design Process: Discovery Phase

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Drug Design Process: Discovery Phase

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Drug Design Process

– creates molecular conformations

– generating high quality molecular

– builds protein structure from sequence

• using homology modelling to model proteins

• when >30% sequence identity exists with

 analyses protein structure

• homology models or experimental (X-

• uses molecular spreadsheet

– determines where on a protein a ligand may bind

(QSAR) and ADME

– computes specialised descriptors

 Descriptors are field strengths around

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

More negative charge

Less steric bulk

 What are the descriptors?

x3,y3,z3 H-bond Donor

 Return all compounds in LeadScreen (50,000

Search Takes 7 seconds and returns 8 compounds

– return molecules which can present a specific arrangement

– Generates 3D molecular structures from 2D

– docks molecules into protein binding

protein binding site

Screen with FlexX

FlexX docking & scoring.

SGI™ Origin® 3800

Data Array Workstations

Screen with DOCK

>2 Million Comps

– builds virtual combinatorial libraries

– have 2 modes of operation

 Combine reagents mode

15 diketones 31 hydrazines 465 products

Filter the database

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