Virtual Screening Approach to Identifying a Novel and Tractable Series of<i>Pseudomonas aeruginosa</i>Elastase Inhibitors
Simon Leiris, David T. Davies, Nicolas Sprynski, Jérôme Castandet, Lilha Beyria, Michael S. Bodnarchuk, Jonathan Sutton, Toby M. G. Mullins, Mark Jones, Andrew K. Forrest, T. David Pallin, Paduri Karunakar, Sathish Kumar Martha, Battu Parusharamulu, Ramesh Ramula, Venkatesh Kotha, Narender Pottabathini, Srinivasu Pothukanuri, Marc Lemonnier, Martin Everett
Abstract
Novel therapies are required to treat chronic bacterial infections in cystic fibrosis (CF) sufferers. The most common pathogen responsible for these infections is Pseudomonas aeruginosa, which persists within the lungs of CF sufferers despite intensive antibiotic treatment. P. aeruginosa elastase (also known as LasB or pseudolysin) is a key virulence determinant that contributes to the pathogenesis and persistence of P. aeruginosa infections in CF patients. The crucial role of LasB in pseudomonal virulence makes it a good target for the development of an adjuvant drug for CF treatment. Herein we discuss the discovery of a new series of LasB inhibitors by virtual screening and computer assisted drug design (CADD) and their optimization leading to compounds 29 and 39 (Ki = 0.16 μM and 0.12 μM, respectively).