Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase
Year: 2022
Type: article
Abstract: Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.
Authors: Kathleen M. Frey, Nicole Bertoletti, Albert H. Chan, Joseph A. Ippolito, Mariela Bollini, Krasimir A. Spasov, William L. Jorgensen, Karen S. Anderson
Institution: Yale University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,950
Funders: U.S. Department of Energy, Yale University, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Biological and Environmental Research, Office of Research Infrastructure Programs, National Institutes of Health, Argonne National Laboratory, Brookhaven National Laboratory
Awards: G101384818, G1021286281, G102163711, G107546177, G1285306620, G1313983767, G1386414003, G1657822250, G1664757510, G171842289, G1867732070, G2004402655, G2287611682, G241279073, G2625084591, G262962599, G2849897711, G2857925935, G3067052642, G3075337988, G3262563802, G357145406, G3728080647, G3924411600, G409777406, G4155925329, G4429385918, G498139845, G5493493709, G5535608740, G5607048534, G5643605200, G5765906131, Mechanism and Inhibition of HIV Reverse Transcriptase, G6059574520, G6389553062, G6476969910, G6848031779, G6918803902, G7103625430, G7463374569, Mechanism and Inhibition of HIV Reverse Transcriptase, G78868261, Computer-Aided Design of Anti-HIV Drugs, G8701900045, G9000161259, Center for Biomolecular Structure (CBMS), Mechanism and Inhibition of HIV Reverse Transcriptase, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G969889393, G993149817
OpenAlex ID: W4212974083