article · Molecules
Targeting the interaction between the tumour suppressor protein p53 and its negative regulator MDM2 is an established strategy in cancer drug discovery. Computational screening evaluated 120 lignans derived from the medicinal plants Ferula sinkiangensis and Justicia procumbens against the MDM2 binding site. Docking simulations identified nine compounds that scored higher than the reference inhibitor Nutlin-3a, alongside satisfactory pharmacokinetic and safety profiles during computational screening. Three specific lignans, named justin A, 6-hydroxy justicidin A, and 6-prime-hydroxy justicidin B, demonstrated superior binding affinities compared to Nutlin-3a. Subsequent molecular dynamics simulations over 100 nanoseconds confirmed that these three candidate compounds formed stable complexes with MDM2. These plant-derived molecules offer potential starting templates for anticancer drug development, although laboratory synthesis and experimental biological validation remain necessary to verify their activity.
The MDM2 protein frequently blocks the action of p53, a critical natural defence against tumour formation. By computationally discovering natural plant compounds that bind tightly to MDM2 and prevent this deactivation, researchers can pinpoint promising chemical structures for anticancer therapies before investing in expensive laboratory synthesis and testing.
This research is at an early computational stage and is distant from clinical use. The findings could assist pharmaceutical chemists and oncology drug discovery programmes seeking new lead compounds to disrupt the MDM2-p53 interaction. Practical development will require chemical synthesis followed by in vitro and in vivo validation to verify biological efficacy, safety, and therapeutic value.
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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.
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DOI: 10.3390/molecules28186665
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