Almoyad Mohammad Ali Abdullah, Wahab Shadma, Mohanto Sourav, Khan Nida Jamil
Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Khamis Mushyt, PO Box. 4536, Abha 61412, Saudi Arabia.
Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia.
ACS Omega. 2024 Apr 9;9(16):18438-18448. doi: 10.1021/acsomega.4c00470. eCollection 2024 Apr 23.
Sortilin (SORT1) is a multifunctional protein intricately involved in atherogenesis, coronary artery disease (CAD), and various neurological disorders. It has materialized as a potential pharmacological target for therapeutic development due to its diverse biological roles in pathological processes. Despite its central role under these conditions, effective therapeutic strategies targeting SORT1 remain challenging. In this study, we introduce a drug repurposing strategy guided by structural insights to identify potent SORT1 inhibitors with broad therapeutic potential. Our approach combines molecular docking, virtual screening, and molecular dynamics (MD) simulations, enabling the systematic evaluation of 3648 FDA-approved drugs for their potential to modulate SORT1. The investigation reveals a subset of repurposed drugs exhibiting highly favorable binding profiles and stable interactions within the binding site of SORT1. Notably, two hits, ergotamine and digitoxin, were carefully chosen based on their drug profiles and subjected to analyze their interactions with SORT1 and stability assessment via all-atom MD simulations spanning 300 ns (ns). The structural analyses uncover the complex binding interactions between these identified compounds and SORT1, offering essential mechanistic insights. Additionally, we explore the clinical implications of repurposing these compounds as potential therapeutic agents, emphasizing their significance in addressing atherogenesis, CAD, and neurological disorders. Overall, this study highlights the efficacy of structure-guided drug repurposing and provides a solid foundation for future research endeavors aimed at the development of effective therapies targeting SORT1 under diverse pathological conditions.
Sortilin（SORT1）是一种多功能蛋白质，与动脉粥样硬化、冠状动脉疾病（CAD）以及各种神经系统疾病密切相关。由于其在病理过程中具有多种生物学作用，它已成为治疗开发的潜在药理学靶点。尽管在这些情况下它起着核心作用，但针对SORT1的有效治疗策略仍然具有挑战性。在本研究中，我们引入了一种基于结构见解的药物再利用策略，以识别具有广泛治疗潜力的强效SORT1抑制剂。我们的方法结合了分子对接、虚拟筛选和分子动力学（MD）模拟，能够系统评估3648种FDA批准的药物调节SORT1的潜力。研究发现了一组再利用药物，它们在SORT1的结合位点表现出非常有利的结合特征和稳定的相互作用。值得注意的是，根据它们的药物特性精心挑选了两种命中药物，麦角胺和洋地黄毒苷，并通过300纳秒（ns）的全原子MD模拟分析它们与SORT1的相互作用以及稳定性评估。结构分析揭示了这些已鉴定化合物与SORT1之间复杂的结合相互作用，提供了重要的机制见解。此外，我们探讨了将这些化合物作为潜在治疗剂进行再利用的临床意义，强调了它们在解决动脉粥样硬化、CAD和神经系统疾病方面的重要性。总体而言，本研究突出了结构导向药物再利用的有效性，并为未来旨在开发针对不同病理条件下SORT1的有效疗法的研究工作奠定了坚实基础。
