Molecular docking of DS-3032B, a mouse double minute 2 enzyme antagonist with potential for oncology treatment development.
Molecular docking of DS-3032B, a mouse double minute 2 enzyme antagonist with potential for oncology treatment development.
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DOI：
10.5306/wjco.v13.i6.496
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发表时间：
2022-06-24
影响因子：
2.8
通讯作者：
Teixeira, Kadima Nayara
中科院分区：
文献类型：
--
作者：
Sales da Mota, Vitor Hugo;de Melo, Fabricio Freire;de Brito, Breno Bittencourt;Franca da Silva, Filipe Antonio;Teixeira, Kadima Nayara
已知p53抑制是癌症预后不良的重要标志，特别是在乳腺、肺、胃和食管的实体瘤;脂肪肉瘤、胶质母细胞瘤和白血病中。由于p53以小鼠双微体2（MDM 2）作为其主要负调节因子，因此本分子对接研究旨在回答以下假设：DS-3032 B与MDM 2之间的相互作用是否足够稳定，从而使该药物被视为有前景的肿瘤抑制剂？通过计算机模拟分析拮抗剂DS-3032 B与其在MDM 2中的结合位点之间的化学键。对于分子对接模拟，选择包含MDM 2（受体）和药物DS-3032 B（配体）结构的文件。MDM 2的三维结构来自Protein Data Bank，DS-3032 B的三维结构来自PubChem数据库。使用AutoDock Tools软件确定网格框的位置和尺寸。在这种情况下，网格的维度涵盖了整个受体。配体DS-3032 B在pH 7.4的生理环境中与MDM 2受体相互作用;因此，为了更可靠地模拟，使用MarvinSketch®软件计算其相互作用，以预测其质子化状态。使用AutoDock Tools软件制备具有和不具有质子化的两种配体用于分子对接。该软件检测药物的扭转点并计算扭转角度。使用连接到维纳软件的AutoDock平台的工具进行分子对接模拟。使用PyMol软件（pymol.org/2）和来自BIOVIA®的Discovery Studio进行参与受体和配体之间相互作用的氨基酸残基以及配体的扭曲、参与相互作用的原子以及相互作用的类型、强度和长度的分析。全局排列表明晶体结构5SWK通过呈现p53结合位点更适合于对接模拟。MDM 2的三维结构5SWK选自蛋白质数据库，DS-3032 B的三维结构选自PubChem（化合物CID：73297272;米拉美坦）。分子对接模拟后，选择质子化和非质子化DS-3032 B的最稳定构象异构体。MDM 2与DS-3032 B之间的相互作用具有高亲和力;在MDM 2/质子化DS-3032 B（-9.9 kcal/mol）和MDM 2/非质子化DS-3032 B构象异构体（-10.0 kcal/mol）之间未观察到亲和力能量的显著差异。MDM 2的16个氨基酸残基与质子化DS-3032 B形成化学键; MDM 2的这16个残基属于p53结合位点区域，为相互作用提供高亲和力，并为药物-蛋白复合物提供稳定性。分子对接表明，DS-3032 B拮抗剂与MDM 2中p53结合位点的相同区域结合，具有高亲和力和稳定性，这表明治疗有效性。
It is known that p53 suppression is an important marker of poor prognosis of cancers, especially in solid tumors of the breast, lung, stomach, and esophagus; liposarcomas, glioblastomas, and leukemias. Because p53 has mouse double minute 2 (MDM2) as its primary negative regulator, this molecular docking study seeks to answer the following hypotheses: Is the interaction between DS-3032B and MDM2 stable enough for this drug to be considered as a promising neoplastic inhibitor? To analyze, in silico, the chemical bonds between the antagonist DS-3032B and its binding site in MDM2. For molecular docking simulations, the file containing structures of MDM2 (receptor) and the drug DS-3032B (ligand) were selected. The three-dimensional structure of MDM2 was obtained from Protein Data Bank, and the one for DS-3032B was obtained from PubChem database. The location and dimensions of the Grid box was determined using AutoDock Tools software. In this case, the dimensions of the Grid encompassed the entire receptor. The ligand DS-3032B interacts with the MDM2 receptor in a physiological environment with pH 7.4; thus, to simulate more reliably, its interaction was made with the calculation for the prediction of its protonation state using the MarvinSketch® software. Both ligands, with and without the protonation, were prepared for molecular docking using the AutoDock Tools software. This software detects the torsion points of the drug and calculates the angle of the torsions. Molecular docking simulations were performed using the tools of the AutoDock platform connected to the Vina software. The analyses of the amino acid residues involved in the interactions between the receptor and the ligand as well as the twists of the ligand, atoms involved in the interactions, and type, strength, and length of the interactions were performed using the PyMol software (pymol.org/2) and Discovery Studio from BIOVIA®. The global alignment indicated crystal structure 5SWK was more suitable for docking simulations by presenting the p53 binding site. The three-dimensional structure 5SWK for MDM2 was selected from Protein Data Bank and the three-dimensional structure of DS-3032B was selected from PubChem (Compound CID: 73297272; Milademetan). After molecular docking simulations, the most stable conformer was selected for both protonated and non-protonated DS-3032B. The interaction between MDM2 and DS-3032B occurs with high affinity; no significant difference was observed in the affinity energies between the MDM2/pronated DS-3032B (-9.9 kcal/mol) and MDM2/non-protonated DS-3032B conformers (-10.0 kcal/mol). Sixteen amino acid residues of MDM2 are involved in chemical bonds with the protonated DS-3032B; these 16 residues of MDM2 belong to the p53 biding site region and provide high affinity to interaction and stability to drug-protein complex. Molecular docking indicated that DS-3032B antagonist binds to the same region of the p53 binding site in the MDM2 with high affinity and stability, and this suggests therapeutic efficiency.
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影响因子：
--
作者：
Chen L;Rousseau RF;Middleton SA;Nichols GL;Newell DR;Lunec J;Tweddle DA
通讯作者：
Tweddle DA
影响因子：
28.5
作者：
Tisato V;Voltan R;Gonelli A;Secchiero P;Zauli G
通讯作者：
Zauli G
影响因子：
3
作者：
Trott, Oleg;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
11.2
作者：
Ishizawa J;Nakamaru K;Seki T;Tazaki K;Kojima K;Chachad D;Zhao R;Heese L;Ma W;Ma MCJ;DiNardo C;Pierce S;Patel KP;Tse A;Davis RE;Rao A;Andreeff M
通讯作者：
Andreeff M
影响因子：
2.3
作者：
Nag S;Qin J;Srivenugopal KS;Wang M;Zhang R
通讯作者：
Zhang R