The research program features state-of-the-art computational design, organic synthesis, biological assaying, and crystallography aimed at delivering clinical candidates with striking potential for combating HIV/AIDS.
The aims are to (1) develop improved technology and understanding for efficient structure-based drug design and (2) apply the technology to create new anti-HIV agents with broad-spectrum potency and excellent pharmacological properties. The research program on structure-based drug design (SBDD) spans fundamental technical advances- in the development of force fields, software for simulations, and enhanced computational methodology, and features applications directed at protein-ligand binding, molecular structure prediction, and inhibitor development. These topics are being pursued with emphasis on development of computational technology for the optimization of lead compounds and for the design of new chemical entities that selectively block HIV replication. Atomic-level computer simulations are used to yield quantitative predictions for the structures and binding energetics of protein-ligand complexes. For inhibitor design, lead generation is facilitated with the ligand-growing program BOMB, and lead optimization is guided by free- energy perturbation (FEP) calculations using Monte Carlo (MC) statistical mechanics. Novel anti-HIV agents in the NNRTI (non-nucleoside reverse transcriptase inhibitors) class were efficiently discovered with high potency towards WT HIV-1 and the K103N HIV-RT variant and with auspicious predicted pharmacological properties. To expand the activity spectrum to a wider range of clinically important variants, new designs are being pursued in three principal templates, U-biHet-NH-Ph, U-5Het-NH-Ph, and U- Het1-L-Het2, where U is an unsaturated hydrophobic group, Het is a heterocycle, and L is a linking chain. The first two motifs orient the U group in the NNRTI binding site in a manner that is well precedented for yielding inhibitors with excellent resistance profiles. The last motif specifically targets Arnold's 2be2 crystal structure, which features an atypical orientation of Tyr181 that promotes avoidance of drug resistance associated with mutations of this residue. Substantial preliminary computational studies have been performed to validate the designs in terms of binding potential and maintenance of good pharmacologica properties. The overriding goal of the powerful combination of design, synthesis, assaying, and crystallography efforts is to deliver the best possible clinical candidates for combating HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044616-14
Application #
8207296
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Turk, Steven R
Project Start
1999-01-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
14
Fiscal Year
2012
Total Cost
$324,413
Indirect Cost
$128,393
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Lee, Won-Gil; Chan, Albert H; Spasov, Krasimir A et al. (2016) Design, Conformation, and Crystallography of 2-Naphthyl Phenyl Ethers as Potent Anti-HIV Agents. ACS Med Chem Lett 7:1156-1160
Jorgensen, William L (2016) Computer-aided discovery of anti-HIV agents. Bioorg Med Chem 24:4768-4778
Cole, Daniel J; Tirado-Rives, Julian; Jorgensen, William L (2015) Molecular dynamics and Monte Carlo simulations for protein-ligand binding and inhibitor design. Biochim Biophys Acta 1850:966-71
Frey, Kathleen M; Puleo, David E; Spasov, Krasimir A et al. (2015) Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants. J Med Chem 58:2737-45
Gray, William T; Frey, Kathleen M; Laskey, Sarah B et al. (2015) Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance. ACS Med Chem Lett 6:1075-9
Lee, Won-Gil; Frey, Kathleen M; Gallardo-Macias, Ricardo et al. (2015) Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 25:4824-7
Mukerjee, Anindita; Iyidogan, Pinar; Castellanos-Gonzalez, Alejandro et al. (2015) A nanotherapy strategy significantly enhances anticryptosporidial activity of an inhibitor of bifunctional thymidylate synthase-dihydrofolate reductase from Cryptosporidium. Bioorg Med Chem Lett 25:2065-7
Lee, Won-Gil; Frey, Kathleen M; Gallardo-Macias, Ricardo et al. (2014) Picomolar Inhibitors of HIV-1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers. ACS Med Chem Lett 5:1259-62
Parker, Christopher G; Dahlgren, Markus K; Tao, Ran N et al. (2014) Illuminating HIV gp120-Ligand Recognition through Computationally-Driven Optimization of Antibody-Recruiting Molecules. Chem Sci 5:2311-2317
Frey, Kathleen M; Gray, William T; Spasov, Krasimir A et al. (2014) Structure-based evaluation of C5 derivatives in the catechol diether series targeting HIV-1 reverse transcriptase. Chem Biol Drug Des 83:541-9

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