Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery

Abstract

Based on the detailed analysis of the binding mode of diarylpyrimidines (DAPYs) with HIV-1 RT, we designed several subseries of novel NNRTIs, with the aim to probe biologically relevant chemical space of solvent-exposed tolerant regions in NNRTIs binding pocket (NNIBP). The most potent compound exhibited significant activity against the whole viral panel, being about 1.5-2.6-fold (WT, EC = 2.44 nM; L100I, EC = 4.24 nM; Y181C, EC = 4.80 nM; F227L + V106A, EC = 17.8 nM) and 4-5-fold (K103N, EC = 1.03 nM; Y188L, EC = 7.16 nM; E138K, EC = 3.95 nM) more potent than the reference drug ETV. Furthermore, molecular simulation was conducted to understand the binding mode of interactions of these novel NNRTIs and to provide insights for the next optimization studies.

Challenges and approaches in the discovery of human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors

“…Modifications were applied on both the central ring (B) and on the four domains considered in the four point‐pharmacophore model of DAPYs (Figure ), that is (i) the hydrophobic domain, (ii) the hydrogen bond interaction domain, (iii) the tolerant region I, and (iv) the tolerant region II (entrance channel). Potent compounds with comparable or higher potency than that of ETV and RPV have been reported over the last years …”

“…Using structure‐based scaffold hopping and molecular hybridization approaches, Kang et al have synthesized several piperidine‐substituted thiophene[3,2‐d]pyrimidine derivatives. Particularly, compound 88 was threefold more potent than ETV against the WT form, five to sevenfold more potent against Y181C, Y188L, E138K, and F227L + V106A and equipotent against L1001 and K103N(Figure ).…”

“…Potent compounds with comparable or higher potency than that of ETV and RPV have been reported over the last years. 32 Structure-based bioisosteric replacement resulted in the discovery of a series of DAPY analogs, such as pyrazinone (77), pyridazine (78), pyridines (79), diarylanilines (80,81), and piperidine-substituted triazine/aniline rings (82,83). These analogs were found to inhibit the replication of WT HIV-1 at low nanomolar concentrations.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Compared with 6 , piperidine‐linked aminopyrimidine derivatives 7 and 8 possess broad potency against resistant mutant viruses (including the K103N/Y181C and Y188L mutants). Compared with ETV, the piperidine‐linked thiophene[3,2‐d]pyrimidines 9 and 10 were exceptionally active against the whole viral panel, including wild‐type (WT), L100I, K103N, E138K, Y181C, Y188L, F227L/V106A, and K103N/Y181C (Figure ) . Importantly, 9 has lower cytotoxicity (CC 50 > 227 μM) and a huge selectivity index (SI) value of >159101.…”

Discovery of potent HIV‐1 non‐nucleoside reverse transcriptase inhibitors by exploring the structure–activity relationship of solvent‐exposed regions I

“…Furthermore, subsequent structural exploration was focused on the solvent‐exposed region I of the NNRTIs binding pocket (NNIBP) and the 4‐aminopiperidine moiety of the K‐5a2 was replaced with cyclohexanediamine, resulting in a conclusion that the linker between the cyclohexanediamine and aryl group exhibited significant influence to anti‐HIV‐1 activity (Figure ). The sulfonamide linker turned out to be the most efficient privileged structure (Kang et al., ; Kang, Ding et al., ). Compound ACS‐9d proved to be the most effective inhibitor and exhibited single‐figure nanomolar activity (EC 50 = 7.1 nM) against the WT HIV‐1 strain.…”