Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India; Department of Chemical Sciences, Indian Institute of Science Education and Research Berhampur, Odisha 760010, India.
Bioorganic Research Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India.
Comput Biol Chem. 2023 Oct;106:107910. doi: 10.1016/j.compbiolchem.2023.107910. Epub 2023 Jun 27.
A novel series of pyrimidine derivatives, bearing modified benzimidazoles at N-1 position, has been designed, synthesized and screened as NNRTIs against HIV and as broad-spectrum antiviral agents. The molecules were screened against different HIV targets using molecular docking experiment. The docking results indicated that the molecules interacted well with the residues Lys101, Tyr181, Tyr188, Trp229, Phe227 and Tyr318 present in NNIBP of HIV-RT protein, formed quite stable complexes and, thus, behaved as probable NNRTIs. Among these compounds, 2b and 4b showed anti-HIV activity with IC values as 6.65 µg/mL (SI = 15.50) and 15.82 µg/mL (SI = 14.26), respectively. Similarly, compound 1a showed inhibitory property against coxsackie virus B4 and compound 3b against different viruses. Molecular dynamics simulation results unequivocally demonstrated the higher stability of the complex HIV-RT:2b than the HIV-RT:nevirapine complex. The MM/PBSA-based binding free energy (-) 114.92 kJ/mol of HIV-RT:2b complex in comparison to that of HIV-RT:nevirapine complex (-) 88.33 kJ/mol, further demonstrated the higher binding strength of 2b and thus, established the potential of compound 2b as a lead molecule as an HIV-RT inhibitor.
设计、合成并筛选了一系列新型嘧啶衍生物，这些衍生物在 N-1 位带有修饰的苯并咪唑，作为 NNRTIs 对抗 HIV 并作为广谱抗病毒药物。使用分子对接实验对这些分子进行了针对不同 HIV 靶点的筛选。对接结果表明，这些分子与 HIV-RT 蛋白的 NNIBP 中存在的残基 Lys101、Tyr181、Tyr188、Trp229、Phe227 和 Tyr318 相互作用良好，形成了相当稳定的复合物，因此可能是 NNRTIs。在这些化合物中，2b 和 4b 表现出抗 HIV 活性，IC 值分别为 6.65µg/mL（SI = 15.50）和 15.82µg/mL（SI = 14.26）。同样，化合物 1a 表现出对柯萨奇病毒 B4 的抑制作用，化合物 3b 对不同病毒表现出抑制作用。分子动力学模拟结果明确证明了 HIV-RT:2b 复合物比 HIV-RT:奈韦拉平复合物具有更高的稳定性。基于 MM/PBSA 的结合自由能 (-) HIV-RT:2b 复合物为 114.92 kJ/mol，而 HIV-RT:奈韦拉平复合物为 (-) 88.33 kJ/mol，进一步证明了 2b 的结合强度更高，从而确立了化合物 2b 作为 HIV-RT 抑制剂的先导分子的潜力。
