重塑药物疗法:在虚拟筛选中使用重塑药物靶向 cathepsin L。

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED Molecular Diversity Pub Date : 2024-10-29 DOI:10.1007/s11030-024-11022-4
Mohammad Khalid, Mohammed H Alqarni, Ahmed I Foudah
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引用次数: 0

摘要

蛋白水解酶与癌症密切相关,在肿瘤生长、血管生成和转移等不同阶段都起着重要作用。尽管针对基质金属蛋白酶(MMPs)做出了努力,但临床试验往往导致各种副作用,如肌肉骨骼疼痛、关节僵硬和肌腱炎,使其成为慢性癌症治疗的次优选择。因此,有必要确定其他蛋白酶靶点,为癌症治疗提供不同的方法。在这些靶点中,Cathepsin L(CatL)是一种溶酶体半胱氨酸蛋白酶,已被确定为与癌症发展和转移有关的治疗靶点。在本研究中,我们采用虚拟筛选和分子动力学(MD)模拟的综合方法,从用于不同治疗的药物库中找出 CatL 的潜在抑制剂。为了实现这一目标,我们对 DrugBank 数据库进行了虚拟筛选,根据它们的对接图谱、有利的对接得分以及与 CatL 结合袋的特异性相互作用,找到了两种针对 CatL 的再利用药物--伊立替康和尼罗替尼。研究人员对伊立替康和尼罗替尼与CatL的结合结构进行了MD模拟,分析表明这两种化合物都能作为CatL抑制剂发挥作用,因为蛋白质与配体之间的相互作用在300 ns内保持稳定。这项研究强调了这些药物与 CatL 结合的稳健性,并表明这些药物可重新用于治疗癌症。这些发现支持使用基于计算机的方法来鉴定新的抑制剂,本研究将成为未来在癌症治疗中靶向 CatL 的实验研究的有用资源。
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Repurposed pharmacotherapy: targeting cathepsin L with repurposed drugs in virtual screening.

Proteolytic enzymes are closely associated with cancer and are important in different phases, including tumor growth, angiogenesis, and metastasis. Despite efforts to target matrix metalloproteases (MMPs), clinical trials have often resulted in various side effects such as musculoskeletal pain, joint stiffness, and tendinitis, making them less optimal for chronic cancer treatment. Thus, there is a need for the identification of other protease targets that would provide different approaches towards the management of cancer. Of these targets, Cathepsin L (CatL) is a lysosomal cysteine protease that has been identified as a therapeutic target that is implicated in cancer development and metastasis. In this study, we performed an integrated approach of virtual screening and molecular dynamics (MD) simulations to identify the potential inhibitors of CatL from a library of drugs that have been used for different treatments. Towards this goal, we performed virtual screening of the DrugBank database and found two repurposed drugs, Irinotecan and Nilotinib, against CatL based on their docking profiles, favorable docking scores, and specific interaction with the CatL binding pocket. MD simulations of the Irinotecan and Nilotinib bound structures with CatL were carried out, and the analysis showed that both these compounds could function as CatL inhibitors as the protein-ligand interactions were stable for 300 ns. This study highlights the robustness of these drugs bound to CatL and indicates that they could be repurposed for the treatment of cancer. These findings endorse the use of computer-based approaches for the identification of new inhibitors, and the present study will be a useful resource for future experimental research towards the targeting of CatL in cancer therapeutics.

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来源期刊
Molecular Diversity
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;
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