Oduselu Gbolahan O, Afolabi Rufus, Ademuwagun Ibitayo, Vaughan Ashley, Adebiyi Ezekiel
Covenant University Bioinformatics Research (CUBRe), Covenant University, Ota, Ogun State, Nigeria.
Department of Chemistry, Covenant University, Ota, Ogun State, Nigeria.
Front Med (Lausanne). 2023 Jan 12;9:1022429. doi: 10.3389/fmed.2022.1022429. eCollection 2022.
() 5-aminolevulinic acid synthase (5-ALAS) is an essential enzyme with high selectivity during liver stage development, signifying its potential as a prophylactic antimalarial drug target. The aim of this study was to identify important potential lead compounds which can serve as inhibitors of 5-ALAS using pharmacophore modeling, virtual screening, qualitative structural assessment, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) evaluation and molecular dynamics simulation. The best model of the tertiary structure of 5-ALAS was obtained using MolProbity, while the following databases were explored for the pharmacophore-based virtual screening: CHEMBL, ChemDiv, ChemSpace, MCULE, MCULE-ULTIMATE, MolPort, NCI Open Chemical Repository, LabNetwork and ZINC databases. 2,621 compounds were screened against the modeled 5-ALAS using AutoDock vina. The post-screening analysis was carried out using Discovery Studio while molecular dynamics simulation was performed on the best hits using NAMD-VMD and Galaxy Europe platform. Compound was observed as the best hit with a binding affinity of -9.9 kcal/mol and predicted Ki of 52.10 nM, engaging in seven hydrogen bonds with the target's active site amino acid residues. The ADMET prediction showed that all ten best hits possessed relatively good pharmacokinetic properties. The qualitative structural assessment of the best hit, , revealed that the presence of two pyridine scaffolds bearing hydroxy and fluorine groups linked by a pyrrolidine scaffold contributed significantly to its ability to have a strong binding affinity with the receptor. The best hit also showed stability in the active site of 5-ALAS as confirmed from the RMSD obtained during the MD simulation.
（）5-氨基乙酰丙酸合酶（5-ALAS）是肝脏阶段发育过程中一种具有高选择性的关键酶，这表明它有潜力成为预防性抗疟药物靶点。本研究的目的是通过药效团建模、虚拟筛选、定性结构评估、ADMET（吸收、分布、代谢、排泄和毒性）评估以及分子动力学模拟，确定可作为5-ALAS抑制剂的重要潜在先导化合物。使用MolProbity获得了5-ALAS三级结构的最佳模型，同时针对基于药效团的虚拟筛选探索了以下数据库：CHEMBL、ChemDiv、ChemSpace、MCULE、MCULE-ULTIMATE、MolPort、NCI开放化学储存库、LabNetwork和ZINC数据库。使用AutoDock vina针对建模的5-ALAS筛选了2621种化合物。使用Discovery Studio进行筛选后分析，同时使用NAMD-VMD和Galaxy Europe平台对最佳命中化合物进行分子动力学模拟。观察到化合物 是最佳命中物，结合亲和力为-9.9 kcal/mol，预测Ki为52.10 nM，与靶点活性位点氨基酸残基形成七个氢键。ADMET预测表明，所有十个最佳命中物都具有相对良好的药代动力学性质。对最佳命中物 的定性结构评估表明，由吡咯烷支架连接的带有羟基和氟基团的两个吡啶支架的存在，对其与受体具有强结合亲和力的能力有显著贡献。如MD模拟期间获得的RMSD所证实，最佳命中物在5-ALAS活性位点也显示出稳定性。
