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

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

Development of novel quinoline based small molecules for targeting the kinases of the DNA damage and repair pathway

by Srimadhavi Ravi, Sugata Bariu and Sivapriya Kirubakara

Targeting the DNA damage and repair pathway � a combinatorial approach towards cancer treatment

by Srimadhavi Ravi, Sugata Barui and Kirubakaran Sivapriy

Targeting the Ataxia Telangiectasia Mutated (ATM) kinase for alleviating cancer

by Srimadhavi Ravi, Sugata Barui and Sivapriya Kirubakara

Targeting the DDR pathway: the pathway to success against the �Emperor of Maladies

by Srimadhavi Ravi, Sugata Barui and Sivapriya Kirubakara

Synthesis and characterization of indole derivatives for inhibition of IMPDH enzyme of H.pylori

by Sachin, Ankush Tyagi, Gayathri Purushothaman, Srimadhavi Ravi and Sivapriya Kirubakara

Exploring the druggability of H. pylori IMPDH

by Gaurav Sharma, Gayathri Purushothaman, Srimadhavi Ravi, Aishwarya Menon, Vijay Thiruvenkatam and Sivapriya Kirubakara

Identification of selective inhibitors of Helicobacter pylori IMPDH as a targeted therapy for the infection

Helicobacter pylori�(H. pylori), the major cause of several gastric disorders has been recognied as a type I carcinogen. By virtue of resistance developed by�H. pylori�strains, currently used antibiotic based treatments rather demonstrate high failure rates. Hence, there is an emerging need for identification of new targets to treat�H. pyloriinfection. Inosine-5?-monophosphate dehydrogenase (IMPDH) has been studied as a potential target to treat�H. pylori�infection. Here, a detailed enzyme kinetic study of recombinant expressed�H. pylori�inosine-5?-monophosphate dehydrogenase (HpIMPDH) is presented. A new in-house synthesized indole-based scaffold is identified as an inhibitor for�HpIMPDH. These indole-based compounds showed non-competitive inhibition against IMP and NAD+�whereas the benzimidazole compounds were found be uncompetitive inhibitors. The new indole scaffold ensures specificity due to its high selectivity for bacterial IMPDH over human IMPDH II. Our work aims to overcome the drawback of existing inhibitors by introducing new indole scaffold for targeting bacterial IMPDH.by Kapil Juvale, Gayathri Purushothaman, Vijay Singh, Althaf Shaik, Srimadhavi Ravi, Vijay Thiruvenkatam and Sivapriya Kirubakara