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首页> 外文会议>ICMSI;International conference of molecular simulations and applied informatics technologies >Design and Discovery of Diarylpyridines and Diarylanilines as Novel Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors
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Design and Discovery of Diarylpyridines and Diarylanilines as Novel Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors

机译：二芳基吡啶和二芳基苯胺作为新型有效的非核苷HIV-1逆转录酶抑制剂的设计和发现

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By using structure-based drug design and isosteric replacement, two sets of derivatives, diarylpyridines (A)1 and diarylanilines (B)2,3, were designed, synthesized and evaluated against wild-type and several drug-resistant HIV-1 viral strains to exploring novel class of next-generation HIV-1 NNRTIs. The results showed that most of the designed compounds exhibited potent anti-HIV-1 activity with EC50 values ranging from low micromolar to nanomolar. However, some compounds displayed expectably high potency with subnanomolar EC50 values against wildtype viral strains, more potent than etravirine (TMC125) in the same assays. Notably, they were also highly effective against infection by multi-RTIresistant strains, thus suggesting highly potential to further develop these compounds as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. Our results also revealed important structure-activity relationship (SAR) conclusions for the two sets of compounds (A and B) and strongly support our hypothesis that an NH2 group on the central ring ortho to the aniline moiety is crucial for interaction with K101 of the NNRTI binding site in HIV-1 RT, likely by forming H-bonds with K101. Furthermore, molecular modeling studies with MM/GBSA (Sybyl 7.2) and CDOCK (DS 2.50) technologies demonstrated the rationality of our hypothesis.
机译：通过使用基于结构的药物设计和等位取代，设计，合成了两组衍生物二芳基吡啶（A）1和二芳基苯胺（B）2,3，并针对野生型和几种耐药HIV-1病毒株进行了评估探索新型的下一代HIV-1 NNRTI。结果表明，大多数设计的化合物均显示出有效的抗HIV-1活性，其EC50值范围从低微摩尔到纳摩尔。但是，某些化合物在抗野生型病毒株方面表现出具有亚纳摩尔级的EC50值的预期高效力，在相同试验中比依曲韦林（TMC125）更有效。值得注意的是，它们还对多种耐多药性菌株的感染非常有效，因此，它们有潜力进一步开发这些化合物，成为具有改善的抗病毒功效和耐药性的新型NNRTIs。我们的研究结果还揭示了两组化合物（A和B）的重要构效关系（SAR）结论，并强烈支持了我们的假设，即与苯胺部分邻位的中心环邻位的NH2基对于与K101的K101相互作用至关重要。 HIV-1 RT中的NNRTI结合位点，可能与K101形成H键。此外，使用MM / GBSA（Sybyl 7.2）和CDOCK（DS 2.50）技术进行的分子建模研究证明了我们的假设的合理性。

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