{"title":"Computational basis of TEAD-3 protein noncovalent inhibition: 3D-QSAR modeling and molecular dynamics simulation","authors":"Bita Kaviani, Marzieh Ghani Dehkordi, Hamed Haghshenas","doi":"10.1002/bkcs.12843","DOIUrl":null,"url":null,"abstract":"<p>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.</p>","PeriodicalId":54252,"journal":{"name":"Bulletin of the Korean Chemical Society","volume":"45 6","pages":"535-550"},"PeriodicalIF":1.7000,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bulletin of the Korean Chemical Society","FirstCategoryId":"92","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/bkcs.12843","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
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.
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.