Scaffold Hopping and Optimization of Thiazole Hybrids as Selective PIN1 Inhibitors: A Computational Study.

IF 1.9 4区 医学 Q3 CHEMISTRY, MEDICINAL
Meeramol C Chellappan, Soumya Vasu, Shriraam Mahadevan, M K Kathiravan, J Saravanan, Soniya Naik, Knolin K Thachil
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引用次数: 0

Abstract

Background: Protein Interacting with NIMA1 (PIN1) is a distinct enzyme, known as a peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the cis-trans isomerization of amide bonds in proteins containing phosphoserine/threonine-proline (pSer/Thr-Pro) motifs, presenting a unique therapeutic opportunity for addressing multiple disorders.

Methods: A series of 140 thiazole compounds were created using the shape similarity technique with the intention of discovering effective PIN1 inhibitors with a new scaffold. The designed compounds were docked into the enzyme's ATP binding site, and the binding free energies for all docked conformations were calculated. The compounds were evaluated for their ADMET and drug-likeness properties. Following the identification of top candidates, molecular dynamics simulations were conducted to investigate the binding dynamics of the highest-scoring compound.

Results: Based on computational findings, sixteen compounds were identified as potential PIN1 inhibitors. Among the sixteen compounds, four (S8Ba, S8Bb, S8Bd, and S8Bd) exhibited the most favorable ADMET profiles and robust interactions with key PIN1 residues. Molecular dynamics simulations confirmed that S8Ba and S8Bd exhibited the most promising activity over 100ns.

Conclusion: The results corroborated the docking outcomes, validating the selected hits as potential PIN1 inhibitors. This breakthrough could influence the development of therapeutic leads for combating diabetes, cancer, and Alzheimer's disease.

支架跳跃和优化噻唑杂种作为选择性PIN1抑制剂:一个计算研究。
背景:与NIMA1相互作用的蛋白质(PIN1)是一种独特的酶,被称为肽酰脯氨酸顺式反式异构酶(PPIase),它催化含有磷酸丝氨酸/苏氨酸脯氨酸(pSer/Thr-Pro)基序的蛋白质中酰胺键的顺式反式异构化,为解决多种疾病提供了独特的治疗机会。方法:利用形状相似技术制备了140个噻唑类化合物,目的是用新的支架寻找有效的PIN1抑制剂。将设计的化合物停靠在酶的ATP结合位点上,并计算所有停靠构象的结合自由能。对化合物的ADMET和药物相似性进行了评价。在确定了最佳候选化合物之后,进行了分子动力学模拟,以研究得分最高的化合物的结合动力学。结果:基于计算结果,16种化合物被确定为潜在的PIN1抑制剂。在16个化合物中,S8Ba、S8Bb、S8Bd和S8Bd表现出最有利的ADMET谱,并与关键的PIN1残基具有较强的相互作用。分子动力学模拟结果表明,S8Ba和S8Bd在100ns以上具有较好的活性。结论:结果证实了对接结果,证实了选定的hit是潜在的PIN1抑制剂。这一突破可能会影响治疗糖尿病、癌症和阿尔茨海默病的发展。
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
Medicinal Chemistry
Medicinal Chemistry 医学-医药化学
CiteScore
4.30
自引率
4.30%
发文量
109
审稿时长
12 months
期刊介绍: Aims & Scope Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.
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