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

被引:8
作者
Alrouji, Mohammed [1 ]
Alhumaydhi, Fahad A. [2 ]
Alsayari, Abdulrhman [3 ,4 ]
Sharaf, Sharaf E. [5 ]
Shafi, Sheeba [6 ]
Anwar, Saleha [7 ]
Shahwan, Moyad [8 ]
Atiya, Akhtar [3 ]
Shamsi, Anas [8 ]
机构
[1] Shaqra Univ, Coll Appl Med Sci, Dept Med Labs, Shaqra, Saudi Arabia
[2] Qassim Univ, Coll Appl Med Sci, Dept Med Labs, Buraydah, Saudi Arabia
[3] King Khalid Univ KKU, Coll Pharm, Dept Pharmacognosy, Abha, Saudi Arabia
[4] King Khalid Univ KKU, Complementary & Alternat Med Unit, Abha, Saudi Arabia
[5] Qura Univ Makkah, Coll Pharm Umm Al, Pharmaceut Chem Dept, Mecca, Saudi Arabia
[6] King Faisal Univ, Coll Appl Med Sci, Dept Nursing, Al Hasa, Saudi Arabia
[7] Jamia Millia Islamia, Ctr Interdisciplinary Res Basic Sci, New Delhi, India
[8] Ajman Univ, Ctr Med & Bioallied Hlth Sci, Ajman, U Arab Emirates
关键词
INHIBITOR; DISCOVERY; MECHANISM;
D O I
10.1371/journal.pone.0293185
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:18
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