Chukwuemeka Prosper Obed, Umar Haruna Isiyaku, Iwaloye Opeyemi, Oretade Oluwaseyi Matthew, Olowosoke Christopher Busayo, Elabiyi Michael Omoniyi, Igbe Festus Omotere, Oretade Oyeyemi Janet, Eigbe Joy Oseme, Adeojo Funmilayo Janet
Department of Biotechnology, School of Sciences (SOS), Federal University of Technology Akure, Akure, Nigeria.
Department of Biochemistry, School of Sciences (SOS), Federal University of Technology Akure, Akure, Nigeria.
J Biomol Struct Dyn. 2022;40(19):9158-9176. doi: 10.1080/07391102.2021.1924267. Epub 2021 May 14.
At present, disrupting p53-MDM2 interactions through small molecule ligands is a promising approach to safe treatment and management of human cancer. Tumor cells unlike the normal cells, are rapidly evolving affecting the efficacy of many approved anti-cancer agents due to drug resistance. Therefore, identifying a potential anticancer compound is crucial. Pharmacophore based virtual screening, followed by molecular docking, ADMET evaluation, and molecular dynamics studies against MDM2 protein was investigated to identify potential ligands that may act as inhibitors. The model (AHRR_1) with survival score (4.176) was selected among the top ranked generated Pharmacophore hypothesis. Validation of the model hypothesis by an external dataset of actives and inactive compounds produced significant validation attributes including; AUC = 0.85, BEDROC = 0.56 at α = 20.0, RIE = 8.18, AUAC = 0.88, and EF of 6.2 at the top 2% of the dataset. The model was use for screening the ZINC database, and the top 1375 hits satisfying the model hypothesis were subjected to molecular docking studies to understand the molecular and structural basis of selectivity of compounds for MDM2 protein. A sub-set of 25 compounds with binding energy lower than the reference inhibitors were evaluated for pharmacokinetic properties. Four compounds (ZINC02639178, ZINC06752762, ZINC38933175, and ZINC77969611) showed the most desired pharmacokinetic profile. Lastly, investigation of the dynamic behaviour of leads-protein complexes through MD simulation showed similar RMSD, RMSF, and H-bond occupancy profile compared to a reference inhibitor, suggesting stability throughout the simulation time. However, ZINC02639178 was found to satisfy the molecular enumeration the most compared to the other three leads. It may emerge as potential treatment option after extensive experimental studies. Communicated by Ramaswamy H. Sarma.
目前，通过小分子配体破坏p53-MDM2相互作用是安全治疗和管理人类癌症的一种有前景的方法。与正常细胞不同，肿瘤细胞正在迅速进化，由于耐药性，影响了许多已批准抗癌药物的疗效。因此，鉴定一种潜在的抗癌化合物至关重要。基于药效团的虚拟筛选，随后进行分子对接、ADMET评估以及针对MDM2蛋白的分子动力学研究，以鉴定可能作为抑制剂的潜在配体。在生成的排名靠前的药效团假设中，选择了生存分数为4.176的模型（AHRR_1）。通过活性和非活性化合物的外部数据集对模型假设进行验证，产生了显著的验证属性，包括：在α = 20.0时，AUC = 0.85，BEDROC = 0.56，RIE = 8.18，AUAC = 0.88，以及在数据集前2%时的富集因子（EF）为6.2。该模型用于筛选ZINC数据库，对满足模型假设的前1375个命中结果进行分子对接研究，以了解化合物对MDM2蛋白选择性的分子和结构基础。对结合能低于参考抑制剂的25种化合物的子集进行药代动力学性质评估。四种化合物（ZINC02639178、ZINC06752762、ZINC38933175和ZINC77969611）显示出最理想的药代动力学特征。最后，通过分子动力学模拟对先导化合物-蛋白质复合物的动态行为进行研究，结果表明与参考抑制剂相比，其均方根偏差（RMSD）、均方根波动（RMSF）和氢键占有率分布相似，表明在整个模拟时间内具有稳定性。然而，与其他三种先导化合物相比，发现ZINC02639178最符合分子枚举。经过广泛实验研究后，它可能成为潜在的治疗选择。由Ramaswamy H. Sarma传达。
