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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Turk, Steven R
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Yale University
Schools of Arts and Sciences
New Haven
United States
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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
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
Mislak, Andrea C; Frey, Kathleen M; Bollini, Mariela et al. (2014) A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase. Biochim Biophys Acta 1840:2203-11
Bollini, Mariela; Frey, Kathleen M; Cisneros, Jose A et al. (2013) Extension into the entrance channel of HIV-1 reverse transcriptase--crystallography and enhanced solubility. Bioorg Med Chem Lett 23:5209-12
Bollini, Mariela; Gallardo-Macias, Ricardo; Spasov, Krasimir A et al. (2013) Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency. Bioorg Med Chem Lett 23:1110-3
Lee, Won-Gil; Gallardo-Macias, Ricardo; Frey, Kathleen M et al. (2013) Picomolar inhibitors of HIV reverse transcriptase featuring bicyclic replacement of a cyanovinylphenyl group. J Am Chem Soc 135:16705-13
Bollini, Mariela; Cisneros, Jose A; Spasov, Krasimir A et al. (2013) Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility. Bioorg Med Chem Lett 23:5213-6
Bailey, Christopher M; Sullivan, Todd J; Iyidogan, Pinar et al. (2013) Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy. J Med Chem 56:3959-68
Jorgensen, William L (2013) Foundations of biomolecular modeling. Cell 155:1199-202

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