The purpose of the research program is to discover new anti-HIV drugs that are potent, safe, easily administered, and long-acting. The approach combines state-of-the-art technology for molecular design, synthetic organic chemistry, biological assaying, and crystallographic determination of structures of the designed molecules bound to their protein target. The PI's research program emphasizes fundamental advances in the development of software and methodology for drug design, detailed modeling of protein-ligand binding, and organic synthesis. The PI's group has developed computational tools to speed lead optimization for potency, while being mindful of the need for desirable pharmacological properties. For the HIV work, collaborations with scientist in the Yale School of Medicine provide the determinations of biological activity in vitro, in human T-cells, and in humanized mouse models, as well as macromolecular structures through protein crystallography. The specific focus is the discovery of inhibitors of HIV-1 reverse transcriptase (HIV-RT), which are a central component of highly active antiretroviral therapy (HAART). The previous grant period witnessed striking advances for our development of the catechol diether series of non-nucleoside inhibitors of HIV-RT. Compounds have been discovered that show remarkable potency, no cytotoxicity, no off-target activity, excellent pharmacological properties, and efficacy in a humanized mouse model of HIV-1 infection. From our extensive crystallographic and modeling studies, thorough knowledge of the binding site has also led to an important new direction of developing the first covalent inhibitors of HIV-RT (CRTIs). We initially targeted the clinically problematic Tyr181Cys RT variants and designed CRTIs that completely knock out activity of the resistant mutants. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell assays. The CRTIs were also shown to be selective for Cys181 and have lower cytotoxicity than the approved drugs efavirenz and rilpivirine. Our compounds are rare examples of targeted covalent allosteric inhibitors, which have enhanced potential for low dosage, low toxicity, and extended duration of action. Extensive discovery, characterization, and development of CRTIs targeting both wild type and resistant forms of HIV-1 are the focus for the next grant period. CRTIs are a new class of anti-HIV agents with potentially profound therapeutic impact.

Public Health Relevance

We develop and apply computational methods for the efficient design of potential drugs. Coupled with synthetic organic chemistry, biological assaying, and protein crystallography, we discover molecules intended for use in combating HIV/AIDS.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Nasr, Mohamed E
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Kudalkar, Shalley N; Beloor, Jagadish; Quijano, Elias et al. (2018) From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection. Proc Natl Acad Sci U S A 115:E802-E811
Dodda, Leela S; Tirado-Rives, Julian; Jorgensen, William L (2018) Unbinding Dynamics of Non-Nucleoside Inhibitors from HIV-1 Reverse Transcriptase. J Phys Chem B :
Chan, Albert H; Lee, Won-Gil; Spasov, Krasimir A et al. (2017) Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography. Proc Natl Acad Sci U S A 114:9725-9730
Kudalkar, Shalley N; Beloor, Jagadish; Chan, Albert H et al. (2017) Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection. Mol Pharmacol 91:383-391
Jorgensen, William L (2016) Computer-aided discovery of anti-HIV agents. Bioorg Med Chem 24:4768-4778
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
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
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
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 1850:966-971

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