Structural Studies and Structure Activity Relationships for Novel Computationally Designed Non-nucleoside Inhibitors and Their Interactions With HIV-1 Reverse Transcriptase

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.

Structure‐based design of diarylpyrimidines and triarylpyrimidines as potent HIV‐1 NNRTIs with improved metabolic stability and drug resistance profiles

“…To gain a more specific explanation of the reduced potency against resistant strains, 8b6 was further conducted molecular modeling analysis, to further explore its binding modes in the RT allosteric pocket. The molecular dynamics simulations were performed with the docked 8b6 ‐RT complexes during 200 ns 22–24 . The RMSD (root mean square deviation) plot (Supporting Information S1: Figure ) illustrated that the binding of ligand‐RT conformations were steady throughout 200 ns simulation, which proved that compound 8b6 was stabilized in the allosteric site of HIV‐1 RT.…”

“…The molecular dynamics simulations were performed with the docked 8b6-RT complexes during 200 ns. [22][23][24] The RMSD (root mean square deviation) plot (Supporting Information S1: Figure 1) illustrated that the binding of ligand-RT conformations were steady throughout 200 ns simulation, which proved that compound 8b6 was stabilized in the allosteric site of HIV-1 RT. Then, the conformations of 8b6 in HIV-1 WT and mutant RTs were investigated.…”

Structure-Based Optimization of 2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Exploiting the Tolerant Regions of the Non-Nucleoside Reverse Transcriptase Inhibitors’ Binding Pocket

“…Briefly, 16b was docked into the cocrystal structures of the RT WT and mutant strains (PDB code, WT: 6c0n; L100I: 3dol; K103N: 6c0o; Y181C: 7so2; Y188L: 6cgf; E138K: 6c0p; V106A + F227L: 6duf; and K103N + Y181C: 6c0r.) with the induced-fit docking module of Schrödinger suite 2022_1. − …”

5-Nitro-3-(2-(4-phenylthiazol-2-yl)hydrazineylidene)indolin-2-one derivatives inhibit HIV-1 replication by a multitarget mechanism of action

“…Recently, it has been shown that Kuwanon-L also inhibits the activity of RT (Martini et al, 2017), opening the way to the development of dual allosteric inhibitors that inhibit both RT and IN. Thanks to the availability in public databases of structural information arising from both RT 3D high-resolution crystalline structures and ligands, both the ligand-based approach and the structure-based approach have been widely used to identify in silico new ligands (Frey et al, 2022). In addition, the resolution of the HIV-1 intasome (Passos et al, 2017;Engelman and Cherepanov, 2021) and the availability of several structures containing INSTI complexed to the Prototype Foamyvirus intasome, which presents a very high level of structural homology with HIV-1, make the study of molecules acting on both systems possible.…”