Sam Dependent Coba Protien as a Drug target; Computational Approaches

Abstract

Emergence of multidrug resistant (MDR) has created a global public health risk. This rise of antimicrobial resistance among human pathogenic bacteria indicates the possible apocalypse in near future. This disastrous situation demands to be addressed and novel antibiotics need to be sought specially against the resistant strain recognized by World Health Organization. The present situation of ineffectiveness of antibiotics in practice because of rapid development of resistant by the pathogenic bacteria demands targeting essential proteins and early introduction of novel therapeutics. Computer aided drug discovery(CADD) has become a prominent and played a major role in the drug discovery for over three decades and has been established as successful methods in screening of the lead compounds against target protein within minimal time frame and with optimum resources. Computational approaches have been used in this study to identify putative drug candidates against the essential Uroporphyrinogen III methyltransferase (CobA) protein of Psuodomonas. Virtual screening of the different ligand libraries consisting of 205 natural products, 462 indole derivatives, 6449 kinase inhibitors and 654 nucleoside mimetics obtained from ADME/Tox and drug likeliness filter identified four lead candidates each from individual library. Ajmaline, 3-(4-fluoro phenyl)-3-(1H-indol-3-yl)-N-(2-morpholino ethyl) propanamide, 1-{4-[2-(2-Phenylethyl) benzoyl] piperazin-1-yl} ethan-1-one and 1-[6-(dimethyl amino) pyrimidin-4-yl]-3[[methyl-[[3-(2-piperidin-ylethoxy)

phenyl] methyl] amino-methyl] pyrrolidin-3-ol were identified as novel therapeutics from the natural products, indole derivatives, kinase inhibitors and nucleoside mimetics respectively. These compounds clearly showed the higher binding affinity than SAM in a protein-ligand complex. Also these compounds showed lower binding efficiency for human hMAT1A protein and larger binding energy for SAM utilizing target protein CobA. Protein ligand interactions from PyMOL, LiGPLOT xi + and residual interaction map obtained using Discovery Studio showed strong bonds like -alkyl bonding in all identified compounds indicating the stability of protein-ligand binding. Further DFT (Density Functional Theory) analysis of frontier molecular orbital studies, calculated parameters and vibrational spectrum of infrared region of studied compounds Ajmaline, 3-(4-fluorophenyl)-3-(1H-indol-3-yl)-N-(2-morpholinoethyl) propanamide, 1-[6-(dimethylamino) pyrimidin-4-yl]-3-[[methyl-[[3-(2-piperidin-ylethoxy) phenyl] methyl] amino-methyl] pyrrolidin-3-ol favoured the molecular docking results at PyRx interface. Thus results indicate that these drug candidates could potentially be used to develop putative drugs against CobA protein of pathogenic bacteria. Also these findings would help in exploring probable therapeutics against other SAM utilizing proteins as well. Keywords: CADD, essential gene, Multidrug resistance, SAM, binding energy