Novel adamantyl clubbed iminothiazolidinones as promising elastase inhibitors: design, synthesis, molecular docking, ADMET and DFT studies.
Atteeque AhmedAamer SaeedSyeda Abida EjazMubashir AzizMuhammad Zaffar HashmiPervaiz Ali ChannarQamar AbbasHussain RazaZahid ShafiqHesham R El-SeediPublished in: RSC advances (2022)
Porcine Pancreatic Elastase (PPE) is a serine protease that is homologous to trypsin and chymotrypsin that are involved in various pathologies like inflammatory disease, Chronic Obstructive Pulmonary Disease (COPD), acute respiratory distress syndrome, cystic fibrosis, and atherosclerosis. PPE if remained uninhibited would lead to digestion of important connective tissue. We developed new structurally diverse series of adamantyl-iminothiazolidinone hybrids to divulge elastase inhibition assay. To identify potent derivatives, in silico screening was conducted and in vitro studies disclosed that the compounds 5a, 5f, 5g, and 5h showed excellent binding energies and low IC 50 values. In silico studies including molecular docking, DFT studies (using the B3LYP/SVP basis set in the gas phase) drug likeness scores and molecular dynamic simulation studies were conducted to evaluate protein-ligand interactions and to determine the stability of top ranked conformation. In silico studies further supported the results of in vitro experiments and suggest these derivatives as novel inhibitors of elastase enzyme.
Keyphrases
- molecular docking
- molecular dynamics simulations
- chronic obstructive pulmonary disease
- case control
- acute respiratory distress syndrome
- cystic fibrosis
- cardiovascular disease
- emergency department
- extracorporeal membrane oxygenation
- lung function
- oxidative stress
- high throughput
- type diabetes
- density functional theory
- small molecule
- binding protein
- transcription factor
- mechanical ventilation
- air pollution
- single cell
- protein protein