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.

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 also predicted the drug likeness (DL) and drug score (DS) of analogues. The molecular docking studies of screened analogues against the protein (PDB ID: 3G5U) were conducted using AutoDock Vina flowing by BIOVIA Discovery Studio for visualizing interactions.Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite.

Results and discussion: The docking scores for the ligands CBZ01, CBZ06, CBZ11, CBZ13, CBZ25, CBZ34, and CBZ38 ranged from -8.0 to -6.4 kcal/mol against the protein (PDB ID: 3G5U). A molecular dynamics (MD) simulation of CBZ01, CBZ13, and CBZ38 was conducted using the Schrödinger suite, revealing that these complexesmaintained stability throughout the 100 ns simulation.

Conclusion: An integrated computational approach combining bioisosteric approach, molecular docking, drug likeness calculations, and MD simulations highlights the promise of ligands CBZ01 and CBZ13 as candidates for the development of potential anticancer agents for the treatment of various cancers.