Munir Maha, Khan Muhammad Umer, Shan Muhammad Adnan, Shah Mohib Ullah, Rehman Raima, Shabbir Chaudhry Ahmed, Alkhtani Hamad M
Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan.
Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan.
Chem Biodivers. 2025 Jul 3:e00980. doi: 10.1002/cbdv.202500980.
CCR5 is a G protein-coupled receptor and a key therapeutic target for human immunodeficiency virus (HIV)-mediated infections, including acquired immunodeficiency syndrome (AIDS). Studies have demonstrated the therapeutic potential of bioactive compounds from ethnomedicinal plants in inhibiting HIV pathogenesis. This study aimed to identify the molecular mechanisms underlying the therapeutic activity of ethnomedicinal phytochemicals against CCR5 through an in silico approach. Molecular docking analysis was conducted using Glide tool of Maestro v12.5. The protein-ligand 3D interactions were modeled and evaluated by structural interaction fingerprinting (SIFt) analysis. ADMET properties of the ligands were assessed separately using SwissADME, pkCSM, and STopTox servers. The geometric parameters of the complexes were determined using density functional theory (DFT) computations. The validated docking protocol yielded a reliable re-docking score of -10.464. Hydroxyl groups and benzene ring π-stacking were identified as contributing to the stability of the complexes. Furthermore, Thr105, Glu283, and Cys178 were observed as key H-bond-accepting residues in phytochemicals against CCR5 receptors. Mol_22 is least toxic, followed by Mol_24 and Mol-31. DFT analysis of Mol-22 revealed its high dipole moments, lower energy gaps, and strong electrophilicity, which was further validated by molecular dynamics (MD) simulations. This study revealed that Mol_22 exhibits acceptable pharmacokinetic features as a potential therapeutic agent for CCR5 inhibition in HIV management.
CCR5是一种G蛋白偶联受体，是人类免疫缺陷病毒（HIV）介导感染（包括获得性免疫缺陷综合征（AIDS））的关键治疗靶点。研究表明，民族药用植物中的生物活性化合物在抑制HIV发病机制方面具有治疗潜力。本研究旨在通过计算机模拟方法确定民族药用植物化学物质对CCR5治疗活性的分子机制。使用Maestro v12.5的Glide工具进行分子对接分析。通过结构相互作用指纹图谱（SIFt）分析对蛋白质-配体三维相互作用进行建模和评估。分别使用SwissADME、pkCSM和STopTox服务器评估配体的ADMET性质。使用密度泛函理论（DFT）计算确定配合物的几何参数。经过验证的对接方案产生了可靠的重新对接分数-10.464。羟基和苯环π堆积被确定为有助于配合物的稳定性。此外，Thr105、Glu283和Cys178被观察为植物化学物质与CCR5受体结合时关键的氢键接受残基。Mol_22毒性最小，其次是Mol_24和Mol-31。对Mol-22的DFT分析显示其具有高偶极矩、较低的能隙和强亲电性，分子动力学（MD）模拟进一步验证了这一点。本研究表明，Mol_22作为HIV治疗中抑制CCR5的潜在治疗剂具有可接受的药代动力学特征。
