Identification of novel potent HIV-1 inhibitors by exploiting the tolerant regions of the NNRTIs binding pocket

• DOI: 10.1016/j.ejmech.2021.113204
• Publication Date: 2021-01-24T06:23:10Z
• Authors: Yanying Sun; Dongwei Kang; Feng Da; Tao Zhang; Pei Li; Baodan Zhang; Erik De Clercq; Christophe Pannec...; Peng Zhan; Xinyong Liu
• Keywords: Docking (animal); Molecular model; Structure–activity relationship; EC50

With our previously identified potent NNRTIs 25a and HBS-11c as leads, series of novel thiophene[3,2-d]pyrimidine and thiophene[2,3-d]pyrimidine derivatives were designed via molecular hybridization strategy. All the target compounds were evaluated for their anti-HIV-1 activity and cytotoxicity in MT-4 cells. Compounds 16a1 and 16b1 turned out to be the most potent inhibitors against WT and mutant HIV-1 strains (L100I, K103N, and E138K), with EC50 values ranging from 0.007 μM to 0.043 μM. Gratifyingly, 16b1 exhibited significantly reduced cytotoxicity (CC50 > 217.5 μM) and improved water solubility (S = 49.3 μg/mL at pH 7.0) compared to the lead 25a (S < 1 μg/mL at pH 7.0, CC50 = 2.30 μM). Moreover, molecular docking was also conducted to rationalize the structure-activity relationships of these novel derivatives and to understand their key interactions with the binding pocket.