Ligand-based modelling for screening natural compounds targeting Minichromosome Maintenance Complex Component-7 for potential anticancer effects

Abstract

Minichromosome Maintenance Complex Component-7 (MCM7) plays a significant role in DNA replication. A comprehensive search of oncogenic databases (UALCAN and KMplot) revealed overexpression or upregulation of MCM7 in a number of cancers (including top prevalent cancer types worldwide). Thus, identification of novel compounds that can decrease expression level of MCM7 can act as a therapeutic strategy against the malignancies in which MCM7 is upregulated. In pursuit of this, computational drug discovery methodology was adopted to identify compounds which can antagonize MCM7 protein. At first, MCM7 protein was docked with control inhibitors of the protein such as Simvastatin, Atorvastatin, Lovastatin, Pravastatin and Breviscapine which showed binding affinity ranging from −8.6 to −7.5 kcal/mol. Ligand-based pharmacophore was generated based on these five compounds. Through ligand-based pharmacophore screening of 11,325 natural compounds, 68 hit compounds were identified. These compounds were docked against MCM7 protein unit. Furthermore, ADMET analysis has been performed to evaluate drug-like properties of all these 68 compounds. Among these, five compounds (Neoandrographolide, Pseudojervine, Isowighteone, Kushenol N and Bucharaine) showed promising ADMET properties and acceptable binding affinities, ranging from −7.7 kcal/mol to −9.3 kcal/mol. Molecular dynamics simulation was performed to evaluate interaction stability of the five compounds with MCM7 inside human body. For Neoandrographolide, Kushenol N and Bucharaine, each system was mostly stable after 15 ns of simulation. Taken together, these compounds can be further evaluated using appropriate cell-based and in vitro models to develop drugs targeting MCM7.

Keywords

• MCM7
• Anti-cancer
• Virtual screening
• Molecular dynamics
• Molecular docking
• Pharmacophore