Repurposed drugs as PCSK9-LDLR disruptors for lipid lowering and cardiovascular disease therapeutics.

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2024-12-08 DOI:10.1007/s11030-024-11063-9

Shelly Singhal Nee Shelly Aggarwal, Divpreet Kaur, Daman Saluja, Kamna Srivastava

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引用次数: 0

Abstract

The PCSK9 protein binds to LDL receptors (LDLR), leading to their degradation and reduced expression on cell surfaces. This decreased the clearance of LDL cholesterol from the bloodstream, thereby increasing the risk of coronary artery diseases. Targeting the PCSK9-LDL receptor interaction is crucial for regulating LDL cholesterol levels and preventing cardiovascular disease. This study aims to screen low molecular weight inhibitors to disrupt the PCSK9-LDLR interaction. We employed a comprehensive approach combining high-throughput virtual screening of DrugBank database, followed by molecular docking studies using CDOCKER and flexible docking methods. The top four lead compounds were further validated through molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA. Finally, the in vitro assay confirmed that Benazepril and Quinapril exhibited the highest potency as PCSK9-LDLR disruptors among the top candidates. These lead compounds have the potential to be repurposed as lipid-lowering agents for the treatment of cardiovascular diseases, offering a promising therapeutic strategy.

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作为PCSK9-LDLR干扰物的再用途药物用于降脂和心血管疾病治疗。

PCSK9蛋白与低密度脂蛋白受体（LDLR）结合，导致其降解并减少细胞表面的表达。这降低了血液中LDL胆固醇的清除率，从而增加了冠状动脉疾病的风险。靶向PCSK9-LDL受体相互作用对于调节LDL胆固醇水平和预防心血管疾病至关重要。本研究旨在筛选低分子量抑制剂来破坏PCSK9-LDLR相互作用。我们采用了结合DrugBank数据库高通量虚拟筛选，CDOCKER和灵活对接方法进行分子对接研究的综合方法。通过分子动力学（MD）模拟和结合自由能计算，进一步验证了前四个先导化合物。最后，体外实验证实，在候选药物中，贝那普利和喹那普利作为PCSK9-LDLR干扰物的效力最高。这些先导化合物有可能被重新用作治疗心血管疾病的降脂剂，提供了一种有前景的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;