Virtual Screening Approach to Identifying a Novel and Tractable Series of Pseudomonas aeruginosa Elastase Inhibitors

Simon Leiris; David T Davies; Nicolas Sprynski; Jérôme Castandet; Lilha Beyria; Michael S Bodnarchuk; Jonathan M Sutton; Toby M G Mullins; Mark W 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

doi:10.1021/acsmedchemlett.0c00554

Virtual Screening Approach to Identifying a Novel and Tractable Series of Pseudomonas aeruginosa Elastase Inhibitors

ACS Med Chem Lett. 2021 Jan 15;12(2):217-227. doi: 10.1021/acsmedchemlett.0c00554. eCollection 2021 Feb 11.

Authors

Simon Leiris¹, David T Davies¹, Nicolas Sprynski¹, Jérôme Castandet¹, Lilha Beyria¹, Michael S Bodnarchuk², Jonathan M Sutton², Toby M G Mullins², Mark W Jones², Andrew K Forrest², T David Pallin², Paduri Karunakar³, Sathish Kumar Martha³, Battu Parusharamulu³, Ramesh Ramula³, Venkatesh Kotha³, Narender Pottabathini³, Srinivasu Pothukanuri³, Marc Lemonnier¹, Martin Everett¹

Affiliations

¹ Antabio SAS, 436 rue Pierre et Marie Curie, 31670 Labège, France.
² Charles River Laboratories, Harlow CM19 5TR, U.K.
³ GVK Biosciences Private Limited, Plot No. 28 A, IDA Nacharam, Hyderabad 500076, India.

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 (K _i = 0.16 μM and 0.12 μM, respectively).