Download FEP-Guidance for Rapid Lead Optimization of Anti-HIV

FEP-Guidance for Rapid Lead Optimization of Anti-HIV
Agents
William L. Jorgensen
Department of Chemistry, Yale University, New Haven, CT 06520-8107
Drug development is being pursued through computer-aided design, synthesis, and
assaying. The design begins with use of the BOMB program, which rapidly constructs
combinatorial libraries given the structure of the target protein and a selected core and
substituents. BOMB grows the analogs inside the protein's binding site, performs a
thorough conformational search, and estimates the analog's binding affinity or activity
using scoring functions. The QikProp program is applied to filter all designed molecules
to insure that they have drug-like properties including solubility and cell permeability.
Monte Carlo/free-energy perturbation (MC/FEP) simulations are then executed to refine
the predictions for the best scoring leads including ca. 1000 explicit water molecules and
extensive sampling for the protein and ligand. Performance of standard series of FEP
calculations for optimization of substituents on an aromatic ring and for choice of
heterocycles is now routine. Recent methodological advances and representative
applications will be presented with emphasis on inhibitor development for HIV reverse
transcriptase. Micromolar leads have been rapidly advanced to extraordinarily potent
anti-HIV agents.
References:
The Many Roles of Computation in Drug Discovery. Jorgensen, W. L., Science 303,
1813-1818 (2004).
Computer-Aided Design of Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase.
Jorgensen, W. L.; Ruiz-Caro, J.; Tirado-Rives, J.; Basavapathruni, A.; Anderson, K. S.;
Hamilton, A. D. Bioorg. Med. Chem. Lett. 16, 663-667 (2006).
Optimization of Pyrimidinyl- and Triazinyl-amines as Non-Nucleoside Inhibitors of HIV-1
Reverse Transcriptase. Thakur, V.; Kim, J. T.; Hamilton, A. D.; Bailey, C. M.; Domaoal, R.
A.;Wang, L.; Anderson,
K. S.; Jorgensen, W. L. Bioorg. Med. Chem. Lett. 16, 5664-5667
(2006).