Debnath Utsab, Kumar Prachi, Agarwal Aakanksha, Kesharwani Ajay, Gupta Satish K, Katti Seturam B
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.
Reproductive Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
Chem Biol Drug Des. 2017 Oct;90(4):527-534. doi: 10.1111/cbdd.12974. Epub 2017 Apr 26.
An in silico method has been used to discover N-hydroxy-substituted 2-aryl acetamide analogs as a new class of HIV-1 integrase inhibitors. Based on the molecular requirements of the binding pocket of catalytic active site, two molecules (compounds 2 and 4b) were designed as fragments. These were further synthesized and biologically evaluated. In vitro potency along with docking studies highlighted compound 4b as an active fragment which was further used to synthesize new leads as HIV-1 integrase inhibitors. Finally, six promising compounds (compounds 5b, 5c, 5e, 6-2c, 6-3b, and 6-5b) were identified by integrase inhibition assay (>50% inhibition). Based on in vitro anti-HIV-1 activity in a reporter gene-based cell assay system, compounds 5d, 6s, and 6k were found as novel HIV-1 integrase inhibitors due to its better selectivity index. Additionally, docking study revealed the importance of H-bond as well as hydrophobic interactions with Asn155, Lys156, and Lys159 which were required for their anti-HIV-1 activity.
一种计算机模拟方法已被用于发现N-羟基取代的2-芳基乙酰胺类似物作为一类新型的HIV-1整合酶抑制剂。基于催化活性位点结合口袋的分子要求，设计了两个分子（化合物2和4b）作为片段。对这些片段进行了进一步的合成和生物学评估。体外活性以及对接研究突出了化合物4b作为一个活性片段，该片段进一步用于合成作为HIV-1整合酶抑制剂的新先导化合物。最后，通过整合酶抑制试验（抑制率>50%）鉴定出六种有前景的化合物（化合物5b、5c、5e、6-2c、6-3b和6-5b）。基于基于报告基因的细胞检测系统中的体外抗HIV-1活性，化合物5d、6s和6k因其更好的选择性指数而被发现是新型HIV-1整合酶抑制剂。此外，对接研究揭示了氢键以及与Asn155、Lys156和Lys159疏水相互作用的重要性，这些相互作用是它们抗HIV-1活性所必需的。
