A probable means to an end: exploring P131 pharmacophoric scaffold to identify potential inhibitors of Cryptosporidium parvum inosine monophosphate dehydrogenase.
ADMET
Cryptosporidium parvum IMPDH
MM/PBSA
P131
Per-residue energy decomposition
Virtual screening
Journal
Journal of molecular modeling
ISSN: 0948-5023
Titre abrégé: J Mol Model
Pays: Germany
ID NLM: 9806569
Informations de publication
Date de publication:
09 Jan 2021
09 Jan 2021
Historique:
received:
12
08
2020
accepted:
27
12
2020
entrez:
10
1
2021
pubmed:
11
1
2021
medline:
28
8
2021
Statut:
epublish
Résumé
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 molecular 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 molecular dynamics simulation and Molecular 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 physicochemical 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 physicochemical and pharmacokinetic properties relative to P131. The identified compounds can serve as a basis for conducting further experimental investigations toward the development of anticryptosporidials, which can overcome the challenges of existing therapeutic options. Graphical abstract P131 and the identified compounds docked in the NAD
Identifiants
pubmed: 33423140
doi: 10.1007/s00894-020-04663-3
pii: 10.1007/s00894-020-04663-3
doi:
Substances chimiques
Enzyme Inhibitors
0
IMP Dehydrogenase
EC 1.1.1.205
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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