Computational predictions of site of metabolism of a pyrrolebased compound as a potential antitubercular agent
Alexandrina Mateeva, Lily Peikova, Maya Georgieva · Journal of Chemical Technology and Metallurgy · 2023
Evaluation of the metabolism profiles of novel molecules is essential for the improvement of their pharmacokinetic characteristics and therapeutic dose.Thus, fast and reliable in silico predictions are being employed in drug design cascade, allowing for screening of large numbers of chemical compounds, and thereafter identifying a small number of promising candidates.The aim of this study was to investigate the potential sites of metabolism (SOMs) of an antitubercular pyrrole-based compound -13b, and to examine the drug binding to several CYP isoforms through in silico approaches.To achieve this objective, two freely available web servers were used -BioTransormers 3.0 and Regioselectivity-WebPredictor (RS-WebPredictor).Schrödinger suite 2021 was utilized for the docking calculations, including the Induced Fit Docking (IFD) and the free binding recalculations with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA).The BioTransformers 3.0 results indicated that the metabolism of 13b proceeds with reactions catalyzed by CYP 1A2, 2C8, 2C9 and 3A4.The web prediction studies demonstrated 13 possible metabolites mostly produced by hydroxylation and O-dealkylation of the latter compound.In addition, another five CYP isozymes (2A6; 2B6; 2C19; 2D6; 2E1) were identified using RS-WebPredictor as possible biotransforming enzymes.The IFD and MM/GBSA calculations demonstrated that the pyrrole-based structure exerts good binding affinity in the active site of CYP 2C8 and 3A4, however, no active poses were generated in CYP1A2.Further in vitro evaluations should be conducted to validate the in silico results.