Shah Syed Sib Tul Hassan, Naeem Iqra, Akram Fatima, Akhtar Muhammad Tayyab, Noor Fatima
Zhejiang Province Key Laboratory of Plant Secondary Metabolism and Regulation, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, 310018, China.
Department of Life Science, School of Science, University of Management and Technology (UMT), Lahore, Pakistan.
Mol Biotechnol. 2025 Feb 13. doi: 10.1007/s12033-025-01389-6.
Naegleria fowleri causes primary amoebic meningoencephalitis (PAM), a lethal disease with a mortality rate of 97%. Current treatment options are limited and often ineffective, highlighting the urgent need for novel therapeutic agents. This study aimed to identify potential inhibitors of the S-adenosyl-L-homocysteine hydrolase (SAHH) enzyme from N. fowleri using an in-silico approach including Molecular Docking, Density Functional Theory (DFT), Molecular Dynamics (MD) simulation, and Molecular Mechanics Generalized Born Surface Area (MMGBSA) analysis. This study included compounds capable of crossing the blood-brain barrier after screening the Asinex Library of 261120 compounds. After molecular docking, ligands had binding energies ranging from - 5.3 to - 11.4 kcal/mol. Only one ligand 2-[(3-Chlorobenzoyl)amino]-N-(2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-5-carboxamide had a better binding energy of - 11.4 kcal/mol as compared to the reference compound adenosine (- 10.1 kcal/mol). DFT calculations revealed HOMO-LUMO energy gaps of 0.14301 eV (α-spin) and 0.07565 eV (β-spin). MD simulations conducted throughout 100 ns confirmed the stable binding and interaction of the ligand with key active site residues, including Asp130, His232, Phe150, Leu200, and Lys68. Stable root-mean-square deviation (RMSD) and continuous interactions between the ligand and critical active site residues were observed. MMGBSA analysis confirmed the ligand's strong binding affinity, indicated by a negative binding energy with substantial lipophilic and Coulombic contributions. The selected ligand demonstrated significant binding affinity, stability, and inhibitory potential against NfSAHH, making it a promising candidate for further development as a therapeutic agent against PAM. The findings reveal novel binding interactions and structural insights into the binding mechanism of NfSAHH inhibitors. By employing a strategic in silico approach, this study provides a robust foundation for identifying and prioritizing potential inhibitors, optimizing resources for experimental validation, and streamlining the drug discovery process.
福氏耐格里阿米巴原虫可引发原发性阿米巴脑膜脑炎（PAM），这是一种致死率高达97%的致命疾病。目前的治疗选择有限且往往无效，凸显了对新型治疗药物的迫切需求。本研究旨在通过包括分子对接、密度泛函理论（DFT）、分子动力学（MD）模拟和分子力学广义玻恩表面积（MMGBSA）分析在内的计算机模拟方法，从福氏耐格里阿米巴原虫中鉴定S - 腺苷 - L - 高半胱氨酸水解酶（SAHH）的潜在抑制剂。在筛选了包含261120种化合物的Asinex文库后，本研究纳入了能够穿过血脑屏障的化合物。分子对接后，配体的结合能范围为 - 5.3至 - 11.4千卡/摩尔。与参考化合物腺苷（ - 10.1千卡/摩尔）相比，只有一种配体2 - [（3 - 氯苯甲酰基）氨基] - N - （2,3 - 二氢 - 1H - 茚 - 5 - 基） - 4 - 甲基 - 1,3 - 噻唑 - 5 - 甲酰胺具有更好的 - 11.4千卡/摩尔的结合能。DFT计算显示，最高占据分子轨道 - 最低未占据分子轨道（HOMO - LUMO）能隙分别为0.14301电子伏特（α自旋）和0.07565电子伏特（β自旋）。在100纳秒内进行的MD模拟证实了配体与关键活性位点残基（包括Asp130、His232、Phe150、Leu200和Lys68）的稳定结合和相互作用。观察到了稳定的均方根偏差（RMSD）以及配体与关键活性位点残基之间的持续相互作用。MMGBSA分析证实了配体具有很强的结合亲和力，其负结合能表明有显著的亲脂性和库仑贡献。所选配体对NfSAHH表现出显著的结合亲和力、稳定性和抑制潜力，使其成为作为抗PAM治疗药物进一步开发的有前景的候选物。这些发现揭示了NfSAHH抑制剂结合机制的新型结合相互作用和结构见解。通过采用战略性的计算机模拟方法，本研究为识别和优先选择潜在抑制剂、优化实验验证资源以及简化药物发现过程提供了坚实的基础。
