Ur Rehman Muhammad Asad, Chuntakaruk Hathaichanok, Amphan Soraat, Suroengrit Aphinya, Hengphasatporn Kowit, Shigeta Yasuteru, Rungrotmongkol Thanyada, Krusong Kuakarun, Boonyasuppayakorn Siwaporn, Aonbangkhen Chanat, Khotavivattana Tanatorn
Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Center of Excellence in Structural and Computation Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
ACS Bio Med Chem Au. 2024 Sep 19;4(5):242-256. doi: 10.1021/acsbiomedchemau.4c00040. eCollection 2024 Oct 16.
Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1' and P2', to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2' substitution was found to be effective, as seen in (1.54 nM), (0.71 nM), (0.31 nM), (0.28 nM), and (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly , which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2' subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.
达芦那韦是一种用于治疗HIV感染的一线药物，但由于新出现的多药耐药（MDR）HIV毒株，它面临着局限性，因此需要开发具有更高活性的类似物。在本研究中，采用了一种组合计算机辅助方法，初步设计了一系列在关键位点P1'和P2'进行修饰的HIV-1蛋白酶抑制剂（PI）类似物，以增强与HIV-1蛋白酶（PR）的相互作用。选择了15个具有良好结合分数的类似物进行合成，并评估其对HIV-1 PR的抑制活性。发现P2'取代基的变化是有效的，如（1.54 nM）、（0.71 nM）、（0.31 nM）、（0.28 nM）和（1.12 nM）所示，在苯基亚砜基序上具有卤素、脂肪族和烷氧基官能团的类似物对HIV-1 PR的抑制作用优于达芦那韦，在Vero和293T细胞系中观察到的细胞毒性最小。此外，计算研究表明，所选类似物具有抑制各种HIV-1 PR突变的潜力，包括I54M和I84V。进一步的结构动力学和能量分析证实了有前景的类似物的稳定性和结合亲和力，特别是，它与HIV-1 PR中的关键残基表现出强烈的相互作用。总体而言，本研究强调了在HIV-1 PR的S2'亚位点引入柔性基团和增强相互作用对于开发有效的达芦那韦类似物以对抗HIV和其他全球健康问题的重要性。
