Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years

Abstract

Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (S-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.

Keywords: AIDS, acquired immunodeficiency syndrome; Bioisosterism; DAPY, diarylpyrimidine; DAPYs; DATA, diaryltriazine; DATAs; DLV, delavirdine; DOR, doravirine; ECD, electronic circular dichroism; EFV, efavirenz; ETR, etravirine; FDA, U.S. Food and Drug Administration; Fragment-based drug design; HAART, highly active antiretroviral therapy; HENT, napthyl-HEPT; HENTs; HEPT, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine; HIV, human immunodeficiency virus; HIV-1; INSTI, integrase inhibitor; Molecular hybridization; NNIBP, NNRTI binding pocket; NNRTI, non-nucleoside reverse transcriptase inhibitor; NNRTIs; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; PK, pharmacokinetic; PROTAC, proteolysis targeting chimera; RPV, rilpivirine; RT, reverse transcriptase; S-DABO, thio-dihydro-alkoxy-benzyl-oxopyrimidine; S-DABOs; SAR, structure–activity relationship; SBDD, structure-based drug design; SFC, supercritical fluid chromatography; SI, selectivity index; Structure-based optimization; UNAIDS, the Joint United Nations Programme on HIV/AIDS; ee, enantiomeric excess.

Graphical abstract

Figure 1

(A) The chemical and three-dimension structures of FDA-approved NNRTI drugs obtained from the crystal complexes with HIV-1 RT showing similar binding conformations: a “butterfly”, “horseshoe”, or “U” mode with a central scaffold and two “wings” (B) Structure of HIV-1 RT (P66/P51) in complex with RNA/DNA and a NNRTI, NVP, are highlighted in different colors (PDB entry: 4PUO).

Figure 2

Structure optimization workflow for the HEPT analogues developed by our group. The modified parts are colored.

Figure 3

(A) Crystal complex of MKC-442 with RT (PDB: 1RT1); and molecular docking models of RT with compounds 1 (B), 2 (C), 4 (D) and 9 (E). The figures were generated by PyMOL.

Figure 4

Structure optimization workflow for the DABO analogues developed by our group. The modified parts are colored.

Figure 5

Molecular docking models of RT with compounds 11 (A), 13 (B), 18 (C), 17-S (D), 17-R (E) and the superposition mode of 17-S and 17-R (F). The figures were generated by PyMOL.

Figure 6

Structure optimization workflow for the DATA analogues developed by our group. The modified parts are colored.

Figure 7

Co-crystal complex of compound 21 with RT (PDB: 1S9E) (A); and molecular docking models of RT with compounds 22 (B), 23 (C), and 24 (D). The figures were generated by PyMOL.

Figure 8

Structure (left “wing”) optimization workflow for the DAPY analogues developed by our group. The modified parts are colored.

Figure 9

Molecular docking models of RT (PDB: 3MEC) with compounds 26 (A), 27 (B), 28 (C) and 33 (F); RT (PDB: 2ZD1) with 29 (D), and 30 (E). The figures were generated by PyMOL.

Figure 10

Linker optimization workflow for the DAPY analogues developed by our group. The modified parts are colored.

Figure 11

Molecular docking models of RT (PDB: 3MEC) with compound 36 (A), 38 (B), 39 (C), 40-R (D), 40-S (E) and 43 (F). The figures were generated by PyMOL.

Figure 12

Molecular hybridization workflow for the DAPY analogues developed by our group. The modified parts are colored.

Figure 13

Molecular docking models of RT (PDB: 3MEC) with compounds 44 (A), 45 (B), 44 and 45 (C), 48 (D), 50 (E) and 52 (F). The figures were generated by PyMOL.

Figure 14

Molecular docking models of compounds 53 and 54 with the HIV-1 WT and E138K/K103N mutant RT (A) WT with 53 (B) E138K mutant RT with 54 (C) K103N mutant RT with 53 (D) WT with 54 (E) E138K mutant RT with 54 (F) K103N mutant RT with 54. The figures were generated by PyMOL.

Figure 15

Other antiviral inhibitors developed by our group. The modified parts are colored.