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

Abstract

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.

Figure 1

SORT1 in complex with the selected molecules. Left panel: SORT1 with ergotamine (yellow), digitoxin (red salmon), and AF38469 (green). Middle panels: a close-up view of SORT1 interaction with ergotamine and digitoxin. Right panels: the surface potential view of the SORT1 binding pocket with the elucidated molecules.

Figure 2

Interactive plots of SORT1 with (A) ergotamine, (B) digitoxin, and (C) AF38469.

Figure 3

SORT1 dynamics and compactness with ergotamine and digitoxin binding. (A) RMSD plot of SORT1 with ergotamine and digitoxin. (B) Average residual fluctuations (RMSF) of SORT1 and its complexes with ergotamine and digitoxin. (C) The time evolution of SORT1 R_g before and after ergotamine and digitoxin binding. (D) SASA distribution plot of SORT1 before and after ergotamine and digitoxin binding.

Figure 4

Dynamics of intramolecular hydrogen bonding. (A) Intramolecular hydrogen bonding in SORT1 before and after ergotamine and digitoxin binding. (B) The PDF plot of intramolecular hydrogen bonding in SORT1.

Figure 5

Intermolecular hydrogen bonding in SORT1 and (A) ergotamine and (B) digitoxin as a time function.

Figure 6

Secondary structure dynamics in (A) SORT1, (B) SORT1–ergotamine, and (C) SORT1–digitoxin as time function.

Figure 7

PCA of SORT1 and its docked complexes. (A) 2D projection and (B) time dynamics of EV1 and EV2.

Figure 8

Free energy landscapes of (A) SORT1, (B) SORT1–ergotamine, and (C) SORT1–digitoxin.

Figure 9

Frontier molecular orbitals (HOMO and LUMO) and optimized geometry of ergotamine, digitoxin, and AF38469.