Molecular Docking and Molecular Dynamics Simulation Studies of Quinoline-3-Carboxamide Derivatives with DDR Kinases–Selectivity Studies towards ATM Kinase

Abstract

Quinoline-3-carboxamides are an essential class of drug-like small molecules that are known to inhibit the phosphatidylinositol 3-kinase-related kinases (PIKK) family kinases. The quinoline nitrogen is shown to bind to the hinge region of the kinases, making them competitive inhibitors of adenosine triphosphate (ATP). We have previously designed and synthesized quinoline-3-carboxamides as potential ataxia telangiectasia mutated (ATM) kinase inhibitors to function as an adjuvant treatment with DNA damaging agents. This article discusses the molecular docking studies performed with these derivatives with the DNA damage and response (DDR) kinases-ATM, ataxia telangiectasia and rad3 related (ATR), and DNA dependent protein kinase catalytic subunit (DNA-PKcs) and highlights their selectivity towards ATM kinase. Docking studies were also performed with mTOR and PI3Kγ, which are close homologs of the DDR kinases. Molecular dynamics simulations were performed for one of the inhibitors against all the enzymes to establish the stability of the interactions involved. Finally, the absorption, distribution, metabolism, and excretion (ADME) properties of the inhibitors were predicted using the QikProp manual in Maestro. In conclusion, the molecules synthesized showed high selectivity towards the ATM kinase in comparison with the other kinases, though the sequence similarity between them was relatively high.