title: Evaluation of Pseudomonas aeruginosa deacetylase LpxC inhibitory activity of dual PDE4-TNFalpha inhibitors: a multiscreening approach.
abstract: In this study, we have focused on the implication of a multiscreening approach in the evaluation of Pseudomonas aeruginosa deacetylase LpxC inhibitory activity of dual PDE4-TNFalpha inhibitors. A genetic function approximation (GFA) directed quantitative structure-activity relationship (QSAR) model was developed for LpxC inhibition on the basis of reported biological activity (Kline and Andersen, J. Med. Chem. 2002, 45, 3112-3129). Subsequently, reported PDE4-TNFalpha inhibitors (Klienman and Campbell, J. Med. Chem. 1998, 41, 266-270) were screened using the QSAR model. Whereby, the compounds were predicted to have equipotent activity with the most potent compound in reported LpxC inhibitor series. A docking analysis of these compounds carried out on the LpxC homology model corroborated the initial results. The compounds were then validated using surface electronic properties analysis and subjected to an adsorption, distribution, metabolism, excretion, and toxicity filter. Taken together, a multiscreening strategy was used to validate potential leads for LpxC inhibition.
authors: Centre of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S Nagar-160 062, Punjab, India.
authors: Rameshwar U
authors: RU
authors: Kadam
authors: Divita
authors: D
authors: Garg
authors: Archana
authors: A
authors: Chavan
authors: Nilanjan
authors: N
authors: Roy
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: C102741:CMKLR1 protein, human; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000581:Amidohydrolases; C514484:LpxC deacetylase, Pseudomonas