Omolabi, Kehinde F. published the artcileA probable means to an end: exploring P131 pharmacophoric scaffold to identify potential inhibitors of Cryptosporidium parvum inosine monophosphate dehydrogenase, Name: 2-((5-Nitrothiazol-2-yl)carbamoyl)phenyl acetate, the main research area is P131 anticryptosporidial antimicrobial IMPDH inhibitor pharmacokinetic cryptosporidiosis Cryptosporidium; ADMET; Cryptosporidium parvum IMPDH; MM/PBSA; P131; Per-residue energy decomposition; Virtual screening.
Compound P131 has been established to inhibit Cryptosporidium parvum′s inosine monophosphate dehydrogenase (CpIMPDH). Its inhibitory activity supersedes that of paromomycin, which is extensively used in treating cryptosporidiosis. Through the per-residue energy decomposition approach, crucial moieties of P131 were identified and subsequently adopted to create a pharmacophore model for virtual screening in the ZINC database. This search generated eight ADMET-compliant hits that were examined thoroughly to fit into the active site of CpIMPDH via mol. docking. Three compounds ZINC46542062, ZINC58646829, and ZINC89780094, with favorable docking scores of – 8.3 kcal/mol, – 8.2 kcal/mol, and – 7.5 kcal/mol, were selected. The potential inhibitory mechanism of these compounds was probed using mol. dynamics simulation and Mol. Mechanics Generalized Poisson Boltzmann Surface Area (MM/PBSA) analyses. Results revealed that one of the hits (ZINC46542062) exhibited a lower binding free energy of – 39.52 kcal/mol than P131, which had – 34.6 kcal/mol. Conformational perturbation induced by the binding of the identified hits to CpIMPDH was similar to P131, suggesting a similarity in inhibitory mechanisms. Also, in silico investigation of the properties of the hit compounds implied superior physicochem. properties with regards to their synthetic accessibility, lipophilicity, and number of hydrogen bond donors and acceptors in comparison with P131. ZINC46542062 was identified as a promising hit compound with the highest binding affinity to the target protein and favorable physicochem. and pharmacokinetic properties relative to P131. The identified compounds can serve as a basis for conducting further exptl. investigations toward the development of anticryptosporidials, which can overcome the challenges of existing therapeutic options. Graphical abstractP131 and the identified compounds docked in the NAD+ binding site of Cryptosporidium parvum IMPDH .
Journal of Molecular Modeling published new progress about Antimicrobial agents. 55981-09-4 belongs to class esters-buliding-blocks, name is 2-((5-Nitrothiazol-2-yl)carbamoyl)phenyl acetate, and the molecular formula is C12H9N3O5S, Name: 2-((5-Nitrothiazol-2-yl)carbamoyl)phenyl acetate.
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