Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors

Abstract

The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6′-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of −7.526 kcal/mol, −7.438 kcal/mol, and −7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (−6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.

Exploration of novel non-purine xanthine oxidase inhibitors based on oxadiazolones by an integrated simulation study

“…Moreover, the solvent-accessible surface area (SASA) is another metric that quantifies the wide-open surface area of a molecule that could be accessed using a solvent system. 53 The SASA values for all systems exhibited significant equilibrium stability, eventually attaining dynamic equilibrium and converging around 490 Å 2 (Fig. 11b).…”

“…Moreover, the solventaccessible surface area (SASA) is another metric that quantifies the wide-open surface area of a molecule that could be accessed using a solvent system. 53 The SASA values for all systems Fig. 7 The overall process of virtual screening.…”

Marine-Derived Compounds for CDK5 Inhibition in Cancer: Integrating Multi-Stage Virtual Screening, MM/GBSA Analysis and Molecular Dynamics Investigations

“…A set of 47,450 2D structures was obtained from a comprehensive marine natural product database. Upon that, the default settings of LigPrep tool in Maestro 12.8 software suite were employed to prepare the collected ligands and decrease probable computational errors [36]. Subsequently, precise, energy-minimized, and refined 3D chemical assemblies were obtained, probable mistakes in the structures of the ligands library were removed, and the possible ionization states were generated at the physiological pH (7 +/−2 ).…”