Molecular dynamics and computational study of Mannich-based coumarin derivatives: potent tyrosine kinase inhibitor

Abstract

The manifestation of bacterial UTI (Urinary Tract Infection) has been predominantly endemic, globally; eventually, the development of new UTI antibacterial agent(s) remains the call of the day. Herein, two series of Mannich-based 4-hydroxy coumarin derivatives, 7a-m and 8a-m were designed by suitable heterocyclic amines condensed with aldehydes. The synthesised molecules were interpreted by ¹H-NMR and ¹³C-NMR spectral analyses with <i>in vitro</i> antibacterial studies. The compound, <i>4-hydroxy-3-((4-hydroxy-3-methoxyphenyl)(morpholino)methyl)-2H-chromen-2-one</i> <b>8l</b> was the significant derivative against pathogenic bacteria <i>Staphylococcus aureus</i> and <i>Escherichia coli</i> with MIC values 12.50 and 25 µM, respectively. Computational assessments with the Lipinski's rule of five, ADMET properties and molecular docking studies revealed that analogues, <b>7f</b>, <b>7l</b>, <b>8d</b>, <b>8j</b> and <b>8k</b> could be potent druggable molecules with significant binding affinity towards bacterial tyrosine kinase, as target. To understand the mode of binding and intrinsic stabilities of potent receptor-ligand complexes, each system was subjected molecular dynamics simulations for 100 ns. Inter-molecular contact analysis and intrinsic hydrogen-bond stability portrayed the analogues <b>8l</b> form a number of non-bonded contacts with the receptor tyrosine kinase being mostly dominated by electrostatic and hydrophobic contacts. The results from the present structure-based designing approach might be a valuable tool towards identification of a new antibacterial drug candidate(s) against UTI in near future.Abbreviations4-HC4-hydroxy coumarinADMETabsorption, distribution, metabolism, excretion, toxicityDCE1,2-dichloroethaneDCMdichloromethaneDMSOdimethyl sulfoxideMDmolecular dynamicsMICminimum inhibitory concentrationNMRnuclear magnetic resonanceNPTisothermal isobaric ensemblesNVTcanonical ensemblesPCAprincipal component analysisPDBprotein data bankRgradius gyrationRMSFroot-mean-square fluctuationsRSMDroot-mean-square deviationUTIurinary Tract InfectionCommunicated by Ramaswamy H. Sarma.