Abstract
In the Fatty Acid Synthase II system, Enoyl-(acyl-carrier-protein) reductase (ENR) encoded by FabI genes is a limiting step enzyme and there is no homologue ENR found in invertebrates which makes it selective target for drug discovery. From Molecular dynamics simulations it was concluded that the solvated protein stabilized at 2.5 ns with larger mobility in the substrate - binding loop and the conformational flexibility of the molecule was revealed. To study the inhibitory effects of novel small molecules in the thiopyridine series, a 2D QSAR model was developed and evaluated for its efficiency. The R2 > 0.96 and Q2 = 0.978 depicted the predictive ability of the models which was determined using a test set of 3 compounds. The receptor-ligand interactions were studied and highest affinity was reported for GCT ID, 343129 (-9.09 Kcal/mol), 341772 (-8.90 Kcal/mol) and 268776 (-8.85 Kcal/mol). These compounds were analysed for their drug like properties and toxicity which projected acceptable blood brain barrier permeation and human intestinal absorption and reduced lipotoxicity. Thus the results suggest further synthesis of new thipyridine series of compounds and experimental testing against drug resistant Staphylococcal infections
Highlights
In the Fatty Acid Synthase II system, Enoyl-(acyl-carrier-protein) reductase (ENR) encoded by FabI genes is a limiting step enzyme and there is no homologue Enoyl acyl carrier protein Reductase (ENR) found in invertebrates which makes it selective target for drug discovery
To gain a notable insight into the intermolecular interactions in biomolecules, an atomic-level structural elucidation is exceedingly helpful. Such time-dependent microscopic behaviour of the bacterial enoyl-acyl carrier protein reductase is calculated by molecular dynamics (MD) simulation and MD simulations predict the movements of atoms present in a molecular system over time, based on their interatomic interactions[9]
The thiopyridine series of compounds that inhibit Staphylococcal growth by inhibiting Enoyl acyl carrier protein Reductase (ENR) action in vitro were used to develop an in-silico model using Quantitative Structure-Activity Relationship (QSAR) studies, and docking studies were conducted on a set of test compounds[12]
Summary
In the Fatty Acid Synthase II system, Enoyl-(acyl-carrier-protein) reductase (ENR) encoded by FabI genes is a limiting step enzyme and there is no homologue ENR found in invertebrates which makes it selective target for drug discovery. Among several enzymes required for catalysing pathways, bacterial Enoyl-acyl carrier protein reductase (ENR), encoded by a highly conserved sequence among diverse bacterial species, FabI genes, is vital and an attractive target for antimicrobial drug discovery[6]. These homologous FabI genes encode the entire ENR activity in gram-positive species such as S. aureus and gram-negative species including Escherichia coli and Haemophilus influenzae7, 8] Time dependent interaction between biological molecules like protein-protein interactions, proteinligand interactions is termed as biological activity. The thiopyridine series of compounds that inhibit Staphylococcal growth by inhibiting Enoyl acyl carrier protein Reductase (ENR) action in vitro were used to develop an in-silico model using QSAR studies, and docking studies were conducted on a set of test compounds[12]
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