Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University , Al-Kharj, Saudi Arabia.
Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University , Al-Kharj, Saudi Arabia.
SAR QSAR Environ Res. 2020 Nov;31(11):837-856. doi: 10.1080/1062936X.2020.1819870.
Sigma-2 (σ) receptor is a transmembrane protein shown to be linked with neurodegenerative diseases and cancer development. Thus, it emerges as a potential biological target for the advancement of anticancer and anti-Alzheimer's agents. The current study was aimed to identify potential σ receptor ligands using integrated computational approaches including homology modelling, combined pharmacophore- and docking-based virtual screening, and molecular dynamics (MD) simulation. Pharmacophore-based screening was conducted against a database composed of 20,523 small natural and natural-like products. In total, 1200 structures were found to satisfy the required pharmacophore features and were then exposed to docking-based screening against the generated homology model of σ receptor. On the basis of the pharmacophore fit scores, docking scores, and mechanism of binding interaction, 20 potential hits were retained. Five promising candidates were selected (SR84, SR823, SR300, SR413, and SR530) on the basis of their binding score and interaction. Further, in silico ADMET profiling of these compounds showed that the selected compounds possess favourable ADME properties with low toxicity risk. The mechanism of interaction of these compounds with σ receptor as well as their binding stability were characterized by MD simulation.
Sigma-2（σ）受体是一种跨膜蛋白，与神经退行性疾病和癌症的发展有关。因此，它成为开发抗癌和抗阿尔茨海默病药物的潜在生物靶点。本研究旨在使用包括同源建模、基于药效团和对接的虚拟筛选以及分子动力学（MD）模拟在内的综合计算方法来鉴定潜在的σ受体配体。基于药效团的筛选针对由 20523 种小分子天然产物和类似天然产物组成的数据库进行。总共发现了 1200 种结构满足所需药效团特征，然后针对生成的σ受体同源模型进行对接筛选。基于药效团拟合分数、对接分数和结合相互作用机制，保留了 20 个潜在的命中化合物。基于它们的结合分数和相互作用，选择了 5 种有前途的候选化合物（SR84、SR823、SR300、SR413 和 SR530）。进一步，这些化合物的计算机 ADMET 分析表明，所选化合物具有良好的 ADME 特性和低毒性风险。通过 MD 模拟研究了这些化合物与σ受体的相互作用机制及其结合稳定性。
