Computer-Aided Drug Design (CADD) Rational Drug Design Structure-Based Drug Design Intelligent Drug Design

Why CADD? 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 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
Molecular Modeling Computer Graphics

Biological Assays
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 Br O
R2

CN O O CH2CH3

Conserved Region

Non-conserved Site 2

R1

O
HA14-1 Attached to glass slides

NH2

Non-conserved Site 1

Non-binding Face

R2 HO 1 H N t-BuMe2SiCl imidazole DMF tBuMe2SiO 2 H N

CHO OH

R2

CHO OH (Ac)2O NH 4-N,N-dimethylamino pyridine Py

R2

CHO OAc NH

HCHO, EtOH

OSiMe2But R2 CHO OAc TBAF THF NH 2,6-lutidine, CH2Cl2 iPr Si OH iPr O iPr Si iPr O iPr Si iPr OTf NH R2 CHO OAc NaOMe NH R2 CHO OH

OSiMe2But

CNCH2COOR1

R1OOC R1OOC R2 O NH CN COOR1 NH2 HF Py / THF; then TMSOMe DMF Cl iPr Si iPr O O Si O Cl Si O O O Si NH R2 O

CN COOR1 NH2 R2

R1OOC

CN COOR1 O NH2

NH

O O Si O

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.