确定包含烷基/芳磺酰基吡咯烷支架的潜在 MMP-2 抑制剂的主要结构属性:一种通过分子动力学模拟分析验证的基于配体的分子建模方法。

IF 2.3 3区 环境科学与生态学 Q3 CHEMISTRY, MULTIDISCIPLINARY
S K Baidya, S Banerjee, B Ghosh, T Jha, N Adhikari
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引用次数: 0

摘要

MMP-2 的过度表达与包括癌症在内的多种疾病密切相关。然而,由于各种不良反应,还没有一种 MMP-2 抑制剂作为候选药物上市。在此,我们对一组磺酰基吡咯烷进行了分子建模验证,然后进行了结合模式分析,以探索发现有前途的 MMP-2 抑制剂所需的关键结构特征。与酯类相比,这项研究揭示了羟酰胺作为潜在锌结合基团的重要性。重要的是,疏水和立体取代基对连接磺酰基的末端芳基有利。结合相互作用研究表明,MMP-2 的 S1'口袋类似于 "篮球穿过篮圈",允许芳基在活性位点适当配合和相互作用,以发挥潜在的 MMP-2 抑制作用。同样,磺酰基吡咯烷分子也是抑制 MMP-2 所必需的良好片段。此外,还报道了一些新型 MMP-2 抑制剂。这些研究表明,吡咯烷环的第 3 位取代对在 S2'口袋内产生相互作用具有重要意义。目前的研究有助于设计和开发潜在的 MMP-2 抑制剂,使其成为未来治疗包括癌症在内的多种疾病的有效候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pinpointing prime structural attributes of potential MMP-2 inhibitors comprising alkyl/arylsulfonyl pyrrolidine scaffold: a ligand-based molecular modelling approach validated by molecular dynamics simulation analysis.

MMP-2 overexpression is strongly related to several diseases including cancer. However, none of the MMP-2 inhibitors have been marketed as drug candidates due to various adverse effects. Here, a set of sulphonyl pyrrolidines was subjected to validation of molecular modelling followed by binding mode analysis to explore the crucial structural features required for the discovery of promising MMP-2 inhibitors. This study revealed the importance of hydroxamate as a potential zinc-binding group compared to the esters. Importantly, hydrophobic and sterical substituents were found favourable at the terminal aryl moiety attached to the sulphonyl group. The binding interaction study revealed that the S1' pocket of MMP-2 similar to 'a basketball passing through a hoop' allows the aryl moiety for proper fitting and interaction at the active site to execute potential MMP-2 inhibition. Again, the sulphonyl pyrrolidine moiety can be a good fragment necessary for MMP-2 inhibition. Moreover, some novel MMP-2 inhibitors were also reported. They showed the significance of the 3rd position substitution of the pyrrolidine ring to produce interaction inside S2' pocket. The current study can assist in the design and development of potential MMP-2 inhibitors as effective drug candidates for the management of several diseases including cancers in the future.

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来源期刊
CiteScore
5.20
自引率
20.00%
发文量
78
审稿时长
>24 weeks
期刊介绍: SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.
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