Alghamdi Youssef Saeed, Mashraqi Mutaib M, Alsalmi Ohud, Alharthi Afaf Awwadh, Gharib Amal F
Department of Biology, Turabah College, Taif University, 21944,, Taif, Saudi Arabia.
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, 61441, Najran, Saudi Arabia.
Med Oncol. 2025 May 9;42(6):206. doi: 10.1007/s12032-025-02723-3.
Lung cancer, the deadliest malignancy worldwide, causes 2.2 million cases and 1.8 million deaths annually, accounting for 18% of cancer deaths. Limited early detection, unaffordable treatments, and drug resistance lead to low survival rates, highlighting the urgent need for developing effective, resistance-proof therapies. In this study, we docked the DrugBank library against Lung Cancer Oxidoreductase, Chaperone, Transferase, and Hydrolase Proteins to identify a multitargeted drug candidate, resulting in identifying a promising drug candidate named Indenopyrazole with docking and MM\GBSA scores ranging from -7.337 to -11.62 and -17.82 to -60.38 kcal/mol, respectively. We also evaluated the interaction pattern of the drug candidate with Molecular Interaction Fingerprints and found that the most interacting residues with its counts are 4TRP, 3ASP, 3GLN, 3GLU, 3LYS, 3PHE, and 3TYR. The pharmacokinetics and comparison with standard values supported the candidate, followed by the density functional theory computations. The study was also validated for the WaterMap for water thermodynamics, and its role in binding pockets has also supported the idea that Indenopyrazole has a multitargeted potency. Further, we extended our studies with 100ns MD Simulation in water to analyse the deviations, fluctuations, and intermolecular interactions, and all the 1000 trajectories were evaluated for total complex energy and binding free energy with MM\GBSA concluding wonderful promising results in support of Indenopyrazole as a multitargeted drug candidate-however, its efficacy needs to be experimentally validated.
肺癌是全球最致命的恶性肿瘤，每年导致220万例病例和180万人死亡，占癌症死亡人数的18%。早期检测有限、治疗费用高昂以及耐药性导致生存率较低，凸显了开发有效、抗耐药疗法的迫切需求。在本研究中，我们将DrugBank库与肺癌氧化还原酶、伴侣蛋白、转移酶和水解酶蛋白进行对接，以确定一种多靶点药物候选物，结果确定了一种名为茚并吡唑的有前景的药物候选物，其对接和MM\GBSA分数分别为-7.337至-11.62和-17.82至-60.38千卡/摩尔。我们还通过分子相互作用指纹评估了该药物候选物的相互作用模式，发现与其相互作用最多的残基及其数量分别为4个色氨酸、3个天冬氨酸、3个谷氨酰胺、3个谷氨酸、3个赖氨酸、3个苯丙氨酸和3个酪氨酸。药代动力学以及与标准值的比较支持了该候选物，随后进行了密度泛函理论计算。该研究还通过水热力学的WaterMap进行了验证，其在结合口袋中的作用也支持了茚并吡唑具有多靶点效力的观点。此外，我们在水中进行了100纳秒的分子动力学模拟以分析偏差、波动和分子间相互作用，并对所有1000条轨迹的总复合物能量和结合自由能进行了MM\GBSA评估，得出了支持茚并吡唑作为多靶点药物候选物的出色且有前景的结果——然而，其疗效需要通过实验验证。
