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

• DOI: 10.1021/acsmedchemlett.8b00054
• Publication Date: 2018-03-01T16:34:47Z
• Authors: Dongwei Kang; Zhao Wang; Heng Zhang; Gaochan Wu; Tong Zhao; Zhongxia Zhou; Zhipeng Huo; Boshi Huang; Da Feng; Xiao Ding; Jian Zhang; Xiaofang Zuo; Lanlan Jing; Wei Luo; Samuel Guma; Dirk Daelemans; Erik De Clercq; Christophe Pannec...; Peng Zhan; Xinyong Liu
• Keywords: EC50; Binding pocket

Based on the detailed analysis of binding mode diarylpyrimidines (DAPYs) with HIV-1 RT, we designed several subseries novel NNRTIs, aim to probe biologically relevant chemical space solvent-exposed tolerant regions in NNRTIs pocket (NNIBP). The most potent compound 21a exhibited significant activity against whole viral panel, being about 1.5–2.6-fold (WT, EC50 = 2.44 nM; L100I, 4.24 Y181C, 4.80 F227L + V106A, 17.8 nM) and 4–5-fold (K103N, 1.03 Y188L, 7.16 E138K, 3.95 more than reference drug ETV. Furthermore, molecular simulation was conducted understand interactions these provide insights for next optimization studies.