药学学报, 2021, 56(2): 545-552
引用本文:
刘红, 曾明辉, 何俊, 欧阳亮. 基于分子对接、定量构效关系和分子动力学研究筛选小分子SIRT1抑制剂[J]. 药学学报, 2021, 56(2): 545-552.
LIU Hong, ZENG Ming-hui, HE Jun, OUYANG Liang. Identification of small molecule sirtuin-1 inhibitors for treating acute myeloid leukemia based on molecular docking, quantitative structure-activity relationships and molecular dynamics[J]. Acta Pharmaceutica Sinica, 2021, 56(2): 545-552.

基于分子对接、定量构效关系和分子动力学研究筛选小分子SIRT1抑制剂
刘红1,2, 曾明辉1,2, 何俊2, 欧阳亮2
1. 邛崃市医疗中心医院药学部, 四川 邛崃 611530;
2. 四川大学华西医院生物治疗国家重点实验室, 四川 成都 610041
摘要:
为了寻找和发现靶向SIRT1的治疗AML的新型先导化合物,本研究利用分子对接与MM-GBSA结合自由能计算进行虚拟筛选,从231 511个天然小分子类药分子库中筛选出8个潜在的SIRT1抑制剂,通过对已有的SIRT1抑制剂分子作为训练集和测试集进行QSAR建模,对筛选出的潜在SIRT1抑制剂分子进行活性预测,随后进行分子动力学模拟验证这些潜在抑制剂与SIRT1蛋白的结合模式与稳定性,最后通过OCI-AML2、OCI-AML3和MV4-11三种AML细胞增殖实验和SIRT1酶活性验证了这些分子的生物活性,发现其中5个分子对3种AML细胞具有不同程度的抑制作用,其中活性最强的化合物ZINC000001774455对AML细胞OCI-AML2的IC50达到2.29 ±0.09 μmol·L-1,1 μmol·L-1浓度下对SIRT1抑制率为65.33%,可作为SIRT1抑制剂先导化合物进行结构修饰,为开发新的AML治疗药物奠定了前期基础。
关键词:    沉默信息调节因子1      分子对接      定量构效关系      分子动力学      抑制剂     
Identification of small molecule sirtuin-1 inhibitors for treating acute myeloid leukemia based on molecular docking, quantitative structure-activity relationships and molecular dynamics
LIU Hong1,2, ZENG Ming-hui1,2, HE Jun2, OUYANG Liang2
1. Department of Pharmacy, Qionglai Medical Center Hospital, Qionglai 611530, China;
2. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
Abstract:
The purpose of this study was to discover novel inhibitors of sirtuin-1 (SIRT1) that could be used in the treatment of acute myeloid leukemia (AML). Eight potential SIRT1 inhibitors were identified from 231 511 natural drug-like molecules by virtual screening-based molecular docking and molecular mechanics-generalized Born surface area (MM-GBSA) calculation of binding free energies. Using existing SIRT1 inhibitor molecules as training and test sets, a series of quantitative structure-activity relationship models were established, and the best quantitative structure-activity relationship (QSAR) model was used to predict the IC50 of these 8 potential inhibitor molecules for SIRT1. Subsequently, molecular dynamics simulations were performed to verify the binding mode and stability of these complexes of potential inhibitors and SIRT1 protein. Finally, the activity of these potential SIRT1 inhibitors was verified by cell proliferation assays of OCI-AML2, OCI-AML3 and MV4-11 cells and SIRT1 enzyme activity assays, and it was found that 5 compounds could inhibit AML cell proliferation. Among them, the most active compound, ZINC000001774455, had an IC50 of 2.29 ±0.09 μmol·L-1 with OCI-AML2 cells, and at a concentration of 1 μmol·L-1, the inhibitory ratio of this compound on SIRT1 protein activity was 65.33%. ZINC000001774455 can be used as a lead compound for the development of new AML treatments.
Key words:    SIRT1    molecular docking    quantitative structure-activity relationship    molecular dynamics    inhibitor   
收稿日期: 2020-09-08
DOI: 10.16438/j.0513-4870.2020-1461
基金项目: 四川省应用基础研究项目(2019YJ0108);国家自然科学基金面上项目(81673290).
通讯作者: 欧阳亮,E-mail:ouyangliang@scu.edu.cn
Email: ouyangliang@scu.edu.cn
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