Repurposing Drugs to Modulate Sortilin: Structure-Guided Strategies Against Atherogenesis, Coronary Artery Disease, and Neurological Disorders.

Autor:	Almoyad MAA; Department of Basic Medical Sciences, College of Applied Medical Sciences, King Khalid University, Khamis Mushyt, PO Box. 4536, Abha 61412, Saudi Arabia., Wahab S; Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia., Mohanto S; Department of Pharmaceutics, Yenepoya Pharmacy College & Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka 575018, India., Khan NJ; Department of Biosciences, Jamia Millia Islamia University, New Delhi 110025, India.
Jazyk:	angličtina
Zdroj:	ACS omega [ACS Omega] 2024 Apr 09; Vol. 9 (16), pp. 18438-18448. Date of Electronic Publication: 2024 Apr 09 (Print Publication: 2024).
DOI:	10.1021/acsomega.4c00470
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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