Identification of novel MCM2 inhibitors from Catharanthus roseus by pharmacoinformatics, molecular docking and molecular dynamics simulation-based evaluation

Nearly all living cells undergo DNA replication in order to duplicate their genome; this multi-step biological process is tightly regulated by different cellular machineries and numerous multi-protein complexes. MCM2 (Minichromosome maintenance protein 2) is a key player in this game and its expression profile has been strongly correlated with cancer formation and progression. Thus, inhibiting MCM2 overexpression can significantly reduce oncogenesis; however, until now there has been no record of any natural drug-like molecule that can overcome MCM2-associated cancer. Therefore, this meticulous study has made an effort to identify novel efficacious drug-like natural compounds with the potential to cease cancer progression, targeting MCM2. This investigation observed 402 different previously identified flavonoids from Catharanthus roseus and studied their potency, efficacy, and safety against MCM2 using a chemoinformatics approach. The initial molecular docking screening identified the compounds that had higher binding affinity with the targeted protein. Further, an in silico pharmacokinetics study and toxicity evaluation were carried out in order to confirm that four natural flavonoids (CHEMSPIDER: 172169, CID: 440832, CID: 8546, CID: 182232) were effective and safe in the human body, as strong inhibitors of MCM2. Lastly, molecular dynamics simulations of the potent inhibitors were executed in order to disclose the stability of CID: 8546 at the active site of the protein. Therefore, the results of this computational approach may act as an initial instruction for future in vitro and in vivo testing carried out in order to identify natural drug-like compounds that can beat cancer, targeting MCM2.