Lead Optimization and Avoidance of Metabolic-perturbing Motif Developing Novel Diarylpyrimidines as Potent HIV-1 NNRTIs
Lead Optimization and Avoidance of Metabolic-perturbing Motif Developing Novel Diarylpyrimidines as Potent HIV-1 NNRTIs
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先导化合物优化和避免代谢干扰基序开发新型二芳基嘧啶作为有效的 HIV-1 NNRTI
DOI：
10.1021/acs.jmedchem.2c00576
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发表时间：
2022
影响因子：
7.3
通讯作者：
Dongwei Kang
中科院分区：
文献类型：
--
作者：
Yanying Sun;Zhenzhen Zhou;Da Feng;Lanlan Jing;Fabao Zhao;Zhao Wang;Tao Zhang;Hao Lin;Hao Song;Erik De Clercq;Christophe Pannecouque;Peng Zhan;Xinyong Liu;Dongwei Kang
非核苷逆转录酶抑制剂（NNRTI）是抗 HIV-1 治疗中不可或缺的一部分。为了发现具有增强的耐药性和改善的药代动力学 (PK) 特性的新型 HIV-1 NNRTI，通过基于共晶结构的药物设计策略生成了一系列新型二芳基嘧啶衍生物。其中，36a对HIV-1 IIIB和一组突变株（L100I、K103N、Y181C、Y188L、E138K、F227L + V106A和RES056）表现出出色的抗病毒活性，EC50范围为2.22至53.3 nM。此外，36被发现对HIV-1 RT具有较高的结合亲和力（KD = 2.50 μM）和抑制活性（IC50 = 0.03 μM）。通过分子对接和分子动力学模拟来合理化这些新型抑制剂的设计并提高其耐药性。此外，36a·HCl表现出良好的PK（T1/2= 5.12 h，F= 12.1%）和安全性（LD50> 2000 mg/kg）。这些都表明36a·HCl可能作为抗HIV-1治疗的新候选药物。
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an indispensable part of anti-HIV-1 therapy. To discover novel HIV-1 NNRTIs with increased drug resistance profiles and improved pharmacokinetic (PK) properties, a series of novel diarylpyrimidine derivatives were generated via the cocrystal structure-based drug design strategy. Among them,36aexhibited outstanding antiviral activity against HIV-1 IIIB and a panel of mutant strains (L100I, K103N, Y181C, Y188L, E138K, F227L + V106A, and RES056), with EC50ranging from 2.22 to 53.3 nM. Besides,36awas identified with higher binding affinity (KD= 2.50 μM) and inhibitory activity (IC50= 0.03 μM) to HIV-1 RT. Molecular docking and molecular dynamics simulation were performed to rationalize the design and the improved drug resistance of these novel inhibitors. Additionally,36a·HClexhibited favorable PK (T1/2= 5.12 h,F= 12.1%) and safety properties (LD50> 2000 mg/kg). All these suggested that36a·HClmay serve as a novel drug candidate anti-HIV-1 therapy.