Designing novel cabozantinib analogues as p-glycoprotein inhibitors to target cancer cell resistance using molecular docking study, ADMET screening, bioisosteric approach, and molecular dynamics simulations

作者：Gajendra Singh Thakur, Ajay Gupta, Dipti Pal, Yogesh Vaishnav, Neeraj Kumar, Sivakumar Annadurai, Sanmati Kumar Jain · 发表于：Frontiers in Chemistry · 年份：2025 · DOI：10.3389/fchem.2025.1543075 · 被引用次数：3 · 研究领域：Drug Transport and Resistance Mechanisms、Computational Drug Discovery Methods、Cancer Research and Treatment

Introduction: One of the foremost contributors to mortality worldwide is cancer. Chemotherapy remains the principal strategy for cancer treatment. A significant factor leading to the failure of cancer chemotherapy is the phenomenon of multidrug resistance (MDR) in cancer cells. The primary instigator of MDR is the over expression of P-glycoprotein (P-gp), a protein that imparts resistance and facilitates the ATP-dependent efflux of various anticancer agents. Numerous efforts have been made to inhibit P-gp function with the aim of restoring the effectiveness of chemotherapy due to its broad specificity. The main objective has been to create compounds that either serve as direct P-gp inhibitors or interact with cancer therapies to modulate transport. Despite substantial in vitro achievements, there are currently no approved drugs available that can effectively "block" P-gp mediated resistance. Cabozantinib (CBZ), a multi-kinase inhibitor, is utilized in the treatment of various carcinomas. CBZ has been shown to inhibit P-gp efflux activity, thereby reversing P-gp mediated MDR. Consequently, P-gp has emerged as a critical target for research in anti-cancer therapies. Methods: The purpose of this study was to computationally identify new andsafer analogues of CBZ using bioisosteric approach, focusing on improved pharmacokinetic properties andreduced toxicity. The physicochemical, medicinal, and ADMET profiles of generated analogues were computed using the ADMETLab 3.0 server. We ...