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 pharmacological 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)
Project #
Application #
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Turk, Steven R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Arts and Sciences
New Haven
United States
Zip Code
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
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
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

Showing the most recent 10 out of 49 publications