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首页> 外文期刊>Medicinal chemistry research: an international journal for rapid communications on design and mechanisms of action of biologically active agents >Discovery of small molecule sirt1 activator using high-throughput virtual screening, molecular dynamics simulation, molecular mechanics generalized born/surface area (MM/GBSA) calculation, and biological evaluation
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Discovery of small molecule sirt1 activator using high-throughput virtual screening, molecular dynamics simulation, molecular mechanics generalized born/surface area (MM/GBSA) calculation, and biological evaluation

机译：使用高通量虚拟筛选，分子动力学仿真，分子力学广义出生/表面积（MM / GBSA）计算和生物学评估，发现小分子SIRT1激活剂

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摘要

Sirt1, namely silent information regulator 1, belongs to a highly conserved family of NAD+-dependent deacetylase which is involved in innumerable human disorders such as obesity, type 2 diabetes, cancer, and aging. Combined high-throughput virtual screening, molecular dynamics simulation, MM/GBSA free energy calculation, and MM/GBSA free energy decomposition analysis approaches were utilized for identification of sirt1 activators. Four compounds with diverse chemical scaffold were retrieved as hits based on docking score and clustering analysis. Our simulations indicated that compound y040-6677 had the highest binding free energies, which could form one hydrogen bond with the residue Asn226. Compound y040-6677 could tightly plug into the hydrophobic allosteric site of sirt1 via strong interaction with the residues Leu215, Thr219, Gln222, Ile223, and Asn226, which were obtained from the MM/GBSA free energy decomposition. These simulation results were consistent with the in vivo enzymatic assay, which implied that compound y040-6677 had a comparable sirt1 activation compared with the reference molecule SRT1720. We hope that compound y040-6677 might represent a promising chemical scaffold for further development of novel sirt1 activators.
机译：SIRT1，即静音信息调节器1属于高度保守的NAD + - 依赖性脱乙酰酶，涉及无数人类疾病，如肥胖，2型糖尿病，癌症和老化。结合高吞吐量虚拟筛选，分子动力学模拟，MM / GBSA自由能量计算和MM / GBSA自由能分解分析方法用于鉴定SIRT1活化剂。根据对接得分和聚类分析，检索具有不同化学支架的四种具有不同化学支架的化合物。我们的模拟表明，化合物Y040-6677具有最高的无限性能量，其可与残留物ASN226形成一个氢键。化合物Y040-6677可以通过与残基Leu215，Thr219，GlN222，ILE223和ASN226的强相互作用紧密插入SIRT1的疏水性变振位点，从MM / GBSA自由能分解获得。这些模拟结果与体内酶测定一致，其暗示化合物Y040-6677与参考分子SRT1720相比具有相当的SIRT1活化。我们希望复合Y040-6677可能代表有前途的化学支架，用于进一步发展新型SIRT1活化剂。

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