Computational basis of TEAD-3 protein noncovalent inhibition: 3D-QSAR modeling and molecular dynamics simulation

IF 1.7 4区 化学 Bulletin of the Korean Chemical Society Pub Date : 2024-04-17 DOI:10.1002/bkcs.12843
Bita Kaviani, Marzieh Ghani Dehkordi, Hamed Haghshenas
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Abstract

The tumor-suppressing phosphorylation cascade is primarily regulated by transcriptional enhanced associate domain (TEAD) transcription factors, and the overexpression of these factors is associated with tumorigenesis and cancer progression. The central pocket of TEAD protein can be targeted by noncovalent inhibitors, and therefore, investigating the interaction patterns for TEAD and its available inhibitors seems essential. In this regard, molecular dynamics simulations were conducted to identify the most potent TEAD3 noncovalent inhibitors and to study TEAD3–inhibitor interaction patterns. We developed a 3D-quantitative structure–activity relationship model to investigate the structure–activity correlation for the available TEAD3 inhibitors. Our results indicated the role of Tyr230, Val317, Thr333, Met367, Cys368, Met371, Phe394, Ile396, Gln398, and Phe416 residues in TEAD3–inhibitor interactions. Dihydropyrazolo pyrimidines and compound 2 were identified as the most potent TEAD3 noncovalent inhibitors. The Comparative Molecular Field Analysis model analysis identified the hydrophobic-favored regions around the pyrazolo[1,5-a]pyrimidin-7(4H)-one ring and the unfavored steric regions around cyclohexane and phenyl groups of dihydropyrazolo pyrimidines.

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TEAD-3 蛋白非共价抑制的计算基础:3D-QSAR 建模和分子动力学模拟
抑制肿瘤的磷酸化级联主要由转录增强关联域(TEAD)转录因子调控,这些因子的过度表达与肿瘤发生和癌症进展有关。TEAD 蛋白质的中心口袋可被非共价抑制剂靶向,因此研究 TEAD 与其可用抑制剂的相互作用模式似乎很有必要。为此,我们进行了分子动力学模拟,以确定最有效的 TEAD3 非共价抑制剂,并研究 TEAD3 与抑制剂的相互作用模式。我们建立了一个三维定量结构-活性关系模型来研究现有 TEAD3 抑制剂的结构-活性相关性。我们的研究结果表明,Tyr230、Val317、Thr333、Met367、Cys368、Met371、Phe394、Ile396、Gln398和Phe416残基在TEAD3-抑制剂相互作用中发挥作用。二氢吡唑嘧啶和化合物 2 被鉴定为最有效的 TEAD3 非共价抑制剂。比较分子场分析模型分析确定了吡唑并[1,5-a]嘧啶-7(4H)-酮环周围的疏水性有利区域和二氢吡唑并嘧啶环己烷基团和苯基基团周围的立体性不利区域。
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来源期刊
Bulletin of the Korean Chemical Society
Bulletin of the Korean Chemical Society Chemistry-General Chemistry
自引率
23.50%
发文量
182
期刊介绍: The Bulletin of the Korean Chemical Society is an official research journal of the Korean Chemical Society. It was founded in 1980 and reaches out to the chemical community worldwide. It is strictly peer-reviewed and welcomes Accounts, Communications, Articles, and Notes written in English. The scope of the journal covers all major areas of chemistry: analytical chemistry, electrochemistry, industrial chemistry, inorganic chemistry, life-science chemistry, macromolecular chemistry, organic synthesis, non-synthetic organic chemistry, physical chemistry, and materials chemistry.
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