Computer-Aided Drug Design (CADD)

Rational Drug Design

Structure-Based Drug Design
Intelligent Drug Design

Why CADD?
H Traditional drug development: random screening, chance discovery
a typical process for a drug: ~12 years and over $300 million!
Limitation: lengthy, expensive, and intellecturally inelegant
H CADD exploits state-of-the-art technologies to speed up the drug
development process

Computer-based Approach to Drug Discovery

Traditional Drug Screening

Random, trial and error
Time consuming
Very expensive
Extremely low yield ( 1 in 100,000)

Computer-based Design
Target specific and structure-based
Fast and automatic
Very low cost
High success rate

A Brief History of CADD

1900: The receptor and lock-and-key concepts
P. Ehrich (1909) and E. Fisher(1894)
1970s: Quantitative structure-activity relationships (QSAR)
Limitations: 2-Dimensional, retrospective analysis
1980s: Beginning of CADD
Molecular Biology
X-ray crystallography, multi-dimensional NMR
Molecular modeling , computer graphics
1990s: Human genome
Bioinformatics
Combinatorial chemistry
High-throughput screening

How does CADD Work?

Target Identification
Genetics
Molecular Biology
Bioinformatics

Structure Determination
X-ray Crystallography
NMR Spectroscopy

Computer-Aided Design

Biological Assays

Molecular Modeling
Computer Graphics

High-Throughput Screening
Computer-Based Screening

Synthetic Chemistry
Peptidomimetics
Combinatorial Chemistry

Clinical Trials

Software for Molecular Modeling

< General purpose molecular modeling (large & small molecules)
molecular mechanics, dynamics and multifunctional programs

< Quantum Chemistry calculations (small molecules)

molecular orbital or quantum mechanical calculations

< Database of molecular structures (large & small molecules)

software for storage and retrieval of molecular structure data

< Molecular graphics (large & small molecules)

programs to visualize molecules

< QSAR (small molecules)

< Others

Software for General Purpose Molecular Modeling

For workstations, minicomputers, and supercomputers (SGI, Sun, Cray, etc.)

AMBER Peter Kollman and coworkers, UCSF

Computer assisted model building, energy minimization,
molecular dynamics, and free energy perturbation calculations.
Midas Plus UCSF Computer Graphics Laboratory
CHARMM Martin Karplus and cowrokers, Harvard
QUANTA/CHARMm Molecular Simulations Inc. (MSI)
molecular/drug design, QSAR, quantum chemistry,
X-ray & NMR data analysis
Insight/DISCOVER Biosym, Inc.
Now MSI and Biosym became Accelrys Inc.
SYBYL Tripos, Inc.
ECEPP (Harold Scheraga and coworkers, Cornell)
MM3 (Norman Allinger and coworkers, Georgia)

Software for General Purpose Molecular Modeling

For personal computers (Apple, Compaq, IBM, etc.)

Alchemy III Tripos, Inc.

Structure building and manipulation, SYBYL energy
minimization, molecular display, conformational searching
Chem3D Pro CambridgeSoft Corp.
Desktop Molecular Modeller Oxford Elec. Publishing
Molecular Modeling Pro WindowChem Software
Energy minimization, QSAR (surface area,
volume, logP), etc.
PC MODEL Serena Software

Molecular Modeling
< Data Analysis
Structural data (X-ray, NMR structure determination)
Biological data (bioinformatics)
Chemical data (QSAR of conventional compound synthesis and
combinatorial chemistry)

< Theory and Prediction

Molecular energy (structure and folding)
Molecular dynamics (conformational changes)
Molecular recognition (ligand and drug design)

De novo Ligand Design Methods

< Fragment location methods
< Site point connection methods
< Fragment connection methods
< Sequential buildup methods
< Whole molecule methods
< Random connection methods

Fragment location Methods

Determine desirable locations of atoms or small fragments

within the active site
< GRID (Goodford et. al.)
< GREEN (Itai et. al.)
< HINT (Kellogg et. al.)

Schematic picture of fragment placement methods

Fragment Connection Methods

Start with previously positioned fragments and find

linkers or scaffolds to connect those fragments and
hold them in a desirable orientation
< Dean, Lewis et. al.
< CAVEAT (Bartett et. al.)
< HOOK (Hubbard et. al.)

Schematic picture of fragment

connection methods

A schematic of three steps

in the HOOK algorithm

Whole Molecule Methods

Fit known compounds into an active site in various

orientations, assessing shape and/or electrostatic
complementarity
< Dock (Kuntz et. al.)
< AUTODOCK (Olsen et. al.)
< Monte Carlo Approaches

Fig -- The procedure for the

computer screening approach
to discover novel organic
inhibitors

Fig. -- The procedure for discovering TJU103 and the structure of this
most potent lead compound bound to the CD4 surface pocket

Computer-aided Drug Design and

Combinatorial Chemistry
< CADD Structural accuracy and specificity
< Combi. Chem. Rapid synthesis and diversity
When combined

More intelligent combinatorial library

More target specific
Higher success rate
Rapid testing & advancing hypothesis and theory

Attached to glass
slides

Binding Face

R2

R1

O
CH3CH2

CN
O

R1

Br
O

CH2CH3

R2

Non-conserved
Site 2

Conserved
Region

NH2

HA14-1
Attached to glass
slides
Non-binding Face

Non-conserved
Site 1

R2
H
N

HO

t-BuMe2SiCl
imidazole
DMF

H
N

tBuMe2SiO

R2

CHO

CHO

OH

CHO
OAc

(Ac)2O

HCHO, EtOH

R2

OH
NH

4-N,N-dimethylamino pyridine
Py

NH

OSiMe2But
R2

R2

CHO
iPr

OAc
TBAF

NH

R2

CHO

CHO
OH

OAc

iPr
Si

OSiMe2But

NH

OTf

NH

NaOMe

CNCH2COOR1

2,6-lutidine, CH2Cl2

THF

iPr

iPr

iPr
Si

OH

R1OOC
R1OOC

CN

R2

NH

iPr
Si

COOR1
O

NH2

Si

R1OOC

CN

R2

COOR1

NH2

NH

HF Py / THF; then TMSOMe

DMF
Cl

iPr

CN

R2

COOR1
O

iPr
Si

NH2

NH

Cl
O

Si

O
O

Si

O
O

Si

Scheme Synthesis and preparation of the HA14-1 combinatorial library

on a glass slide.

Further Readings
Rational Drug Design, Springer-Verlag, New York, 1999
Computer-aided Drug Design, Dekker, Inc., 1999
Guidebook on Molecular Modeling in Drug Design,
Academic Press.
Reviews in Computational Chemistry, VCH Publishers,
Inc., 1996
P.J. Whittle and T.L. Blundell, Annu. Rev. Biophys.
Biomol. Struct., 23, 349 (1994). Protein Structure-Based
Drug Design.
I.D. Kuntz, Science, 257, 1078 (1992). Structure-based
strategies for drug design and discovery.
W.C. Guida, Curr. Opin. Struct. Biol., 4, 777 (1994).
Software for structure-based drug design.