A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases
1
Issued Date
2023-01-01
Resource Type
ISSN
13811991
eISSN
1573501X
Scopus ID
2-s2.0-85145825750
Pubmed ID
36617352
Journal Title
Molecular Diversity
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular Diversity (2023)
Suggested Citation
Eurtivong C., Zimmer C., Schirmeister T., Butkinaree C., Saruengkhanphasit R., Niwetmarin W., Ruchirawat S., Bhambra A.S. A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases. Molecular Diversity (2023). doi:10.1007/s11030-023-10600-2 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/81732
Title
A structure-based virtual high-throughput screening, molecular docking, molecular dynamics and MM/PBSA study identified novel putative drug-like dual inhibitors of trypanosomal cruzain and rhodesain cysteine proteases
Other Contributor(s)
Abstract
Virtual screening a collection of ~ 25,000 ChemBridge molecule collection identified two nitrogenous heterocyclic molecules, 12 and 15, with potential dual inhibitory properties against trypanosomal cruzain and rhodesain cysteine proteases. Similarity search in DrugBank found the two virtual hits with novel chemical structures with unreported anti-trypanosomal activities. Investigations into the binding mechanism by molecular dynamics simulations for 100 ns revealed the molecules were able to occupy the binding sites and stabilise the protease complexes. Binding affinities calculated using the MM/PBSA method for the last 20 ns showed that the virtual hits have comparable binding affinities to other known inhibitors from literature suggesting both molecules as promising scaffolds with dual cruzain and rhodesain inhibition properties, i.e. 12 has predicted ΔGbind values of − 38.1 and − 38.2 kcal/mol to cruzain and rhodesain, respectively, and 15 has predicted ΔGbind values of − 34.4 and − 25.8 kcal/mol to rhodesain. Per residue binding free energy decomposition studies and visual inspection at 100 ns snapshots revealed hydrogen bonding and non-polar attractions with important amino acid residues that contributed to the ΔGbind values. The interactions are similar to those previously reported in the literature. The overall ADMET predictions for the two molecules were favourable for drug development with acceptable pharmacokinetic profiles and adequate oral bioavailability. Graphical Abstract: [Figure not available: see fulltext.]