Computational Screening of Natural Compounds for Identification of Potential Anti-Cancer Agents Targeting MCM7 Protein.

Mohammad Y. Alshahrani,Nadiyah M. Alabdallah,Mohammed Asiri,Tahani M. Almeleebia,Irfan Ahmad,Arshiya Akeel,Najla A. Alshahrani,Mohd Saeed,Kholoud M. Alshahrani,Munazzah Tasleem

doi:10.3390/molecules26195878

Abstract

Minichromosome maintenance complex component 7 (MCM7) is involved in replicative licensing and the synthesis of DNA, and its overexpression is a fascinating biomarker for various cancer types. There is currently no effective agent that can prevent the development of cancer caused by the MCM7 protein. However, on the molecular level, inhibiting MCM7 lowers cancer-related cellular growth. With this purpose, this study screened 452 biogenic compounds extracted from the UEFS Natural Products dataset against MCM protein by using the in silico art of technique. The hit compounds UEFS99, UEFS137, and UEFS428 showed good binding with the MCM7 protein with binding energy values of −9.95, −8.92, and −8.71 kcal/mol, which was comparatively higher than that of the control compound ciprofloxacin (−6.50). The hit (UEFS99) with the minimum binding energy was picked for molecular dynamics (MD) simulation investigation, and it demonstrated stability at 30 ns. Computational prediction of physicochemical property evaluation revealed that these hits are non-toxic and have good drug-likeness features. It is suggested that hit compounds UEFS99, UEFS137, and UEFS428 pave the way for further bench work validation in novel inhibitor development against MCM7 to fight the cancers.

Highlights

Cancer chemotherapy has historically targeted DNA replication because cancer cells proliferate uncontrollably compared to most non-cancerous cells [1]
Natural compounds were accessed from the ZINC database under the catalogue “UEFS Natural Products” which is a collection of biogenic compounds with an “In-Vitro” activity level [23]. 452 biogenic compounds were extracted from the UEFS Natural Products dataset and refined in Discover Studio 2020 using the ligand preparation tool
Since cancer cells proliferate uncontrollably compared to non-cancerous cells, DNA replication was long regarded as a key target for cancer chemotherapy

Summary

Introduction

Cancer chemotherapy has historically targeted DNA replication because cancer cells proliferate uncontrollably compared to most non-cancerous cells [1]. Small molecule inhibitors that primarily target the leading or lagging strand of DNA synthesis were employed earlier to clinically block the proliferation of uncontrolled cancer cells [3]. These compounds were shown to be chemotherapeutic, they are aimed at both normal and malignant DNA replication and frequently have adverse effects. The toroidal Mcm complex, unlike other replicative helicases, is composed of six distinct and essential subunits (numbered 2–7) [2]. Heliquinomycin was identified as an inhibitor of a non-physiological Mcm sub complex (Mcm467) [9,10] and reduces cancer cell proliferation in vitro, implying that Mcm inhibitors possess therapeutic potential [11]. Due to the shortcomings of existing clinical trials, phytochemical compounds are intensely focused on treating different cancers [13]

Methods

Discussion

Conclusion