Targeting Sirtuin 1 for therapeutic potential: Drug repurposing approach integrating docking and molecular dynamics simulations

Author:

Alrouji Mohammed,Alhumaydhi Fahad A.ORCID,Alsayari Abdulrhman,Sharaf Sharaf E.ORCID,Shafi Sheeba,Anwar Saleha,Shahwan Moyad,Atiya Akhtar,Shamsi AnasORCID

Abstract

Identifying novel therapeutic agents is a fundamental challenge in contemporary drug development, especially in the context of complex diseases like cancer, neurodegenerative disorders, and metabolic syndromes. Here, we present a comprehensive computational study to identify potential inhibitors of SIRT1 (Sirtuin 1), a critical protein involved in various cellular processes and disease pathways. Leveraging the concept of drug repurposing, we employed a multifaceted approach that integrates molecular docking and molecular dynamics (MD) simulations to predict the binding affinities and dynamic behavior of a diverse set of FDA-approved drugs from DrugBank against the SIRT1. Initially, compounds were shortlisted based on their binding affinities and interaction analyses to identify safe and promising binding partners for SIRT1. Among these candidates, Doxercalciferol and Timiperone emerged as potential candidates, displaying notable affinity, efficiency, and specificity towards the binding pocket of SIRT1. Extensive evaluation revealed that these identified compounds boast a range of favorable biological properties and prefer binding to the active site of SIRT1. To delve deeper into the interactions, all-atom MD simulations were conducted for 500 nanoseconds (ns). These simulations assessed the conformational dynamics, stability, and interaction mechanism of the SIRT1-Doxercalciferol and SIRT1-Timiperone complexes. The MD simulations illustrated that the SIRT1-Doxercalciferol and SIRT1-Timiperone complexes maintain stability over a 500 ns trajectory. These insightful outcomes propose that Doxercalciferol and Timiperone hold promise as viable scaffolds for developing potential SIRT1 inhibitors, with implications for tackling complex diseases such as cancer, neurodegenerative disorders, and metabolic syndromes.

Funder

Deanship of Scientific Research, King Khalid University

Publisher

Public Library of Science (PLoS)

Subject

Multidisciplinary

Reference47 articles.

1. Towards precision medicine in the clinic: from biomarker discovery to novel therapeutics;DC Collins;Trends in pharmacological sciences,2017

2. Inflammaging and oxidative stress in human diseases: from molecular mechanisms to novel treatments;L Zuo;International journal of molecular sciences,2019

3. Phenotypic vs. target‐based drug discovery for first‐in‐class medicines;D. Swinney;Clinical Pharmacology & Therapeutics,2013

4. Drug repurposing: progress, challenges and recommendations.;S Pushpakom;Nature reviews Drug discovery.,2019

5. A review of computational drug repurposing;K. Park;Translational and clinical pharmacology,2019

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