Identification of potential inhibitors of ATM kinase: pharmacoinformatics and molecular dynamics simulation approach. Issue 5 (24th March 2023)

• Record Type: Journal Article
• Authors: Inchara Moodbagil, C.; Mahmood, Riaz; Kumaraswamy, H.M.; Chandramohan, Vivek; Dammalli, Manjunath; Sharath, R.; Meghana, P.; Sandeep Kumar Jain, R.; Prashanth, N.; Samartha, J.R.
• Is Part Of: Molecular simulation. Volume 49:Issue 5(2023)
• Page Start: 472
• Page End: 480
• Publication Date: 2023-03-24
• Subjects: Ataxia-Telangiectasia Mutated kinase -- Genus Miliusa -- Rhamnazin -- Molecular Dynamics Simulation; Molecular dynamics -- Computer simulation -- Periodicals; Statistical mechanics -- Computer simulation -- Periodicals; 539.6
• DOI: 10.1080/08927022.2023.2165694
• Languages: English
• ISSNs: 0892-7022

Abstract

ABSTRACT: Ataxia-Telangiectasia Mutated kinase (ATM kinase) is a well-established protein, maintains genome integrity and modulates cellular responses to DNA breakage. It is acknowledged as a master regulator of Double-Strand Breaks (DSB) and redox sensor. In a variety of human malignancies, cells exhibit resistance to radiation and chemotherapeutic approach and thus, the suppression of ATM kinase is a promising strategy to promote cellular sensitivity. Several Miliusa plants are used for traditional medication and reveal appreciable cytotoxicity against tumours. The objective of this study is to achieve sensitization to resistant cells by identifying potent bioactive inhibitors which can block the activity of ATM kinase. Hence, we considered 14 phytoconstituents from genus Miliusa . In this study, we performed Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET), drug-likeliness prediction, molecular docking and Molecular Dynamics Simulation (MDS). The docking results were evaluated based on free energy binding (Δ G ) and it revealed that conocarpan, epicatechin, rhamnazin and rhamnetin found to be potent inhibitors of ATM kinase. The MD simulation results showed the detailed structure and residue level changes upon binding with novel inhibitors. The present investigation proposes, rhamnazin as an efficient inhibitor owing to significant interaction with ATM kinase by exhibiting better binding energy of −29.72 kJ/mol than standard KU-55933 with −17.76 kJ/mol.