The emergence of M. tuberculosis strains that are resistant to front line antimicrobacterial drugs have greatly complicated efforts to control the spread of tuberculosis (TB). Among the most promising strategies yet developed for overcoming the problem of resistance was the discovery of new non β-lactam scaffolds inhibitors of β-lactamases. Herein, we present a new platform of research aimed to discover novel small organic molecules, containing the non β-lactam scaffolds by employing a combination of molecular docking and in vitro enzyme inhibition assays. We first focused on finding of novel 3D-pharmacophores and fragments from the family of diphenyl, aromatic ketone, hydroxy-phenyl derivatives and stilbene, all previously described by others to exhibit antibacterial activity. The discovery of these novel pharmacophore features allowed us to further optimize a focused structure-based drug design (SBDD) platform by selectively defining the chemical space of the ligand libraries during in silico screening and docking employing Autodock Vina and the on-line server Pharmit (pharmit.csb.pitt.edu). We screened databases covering a wide landscape of chemical libraries from ChEMBL/MolPort/ZINC and performe molecular docking using available X-Ray structures of beta lactamases in complex with selected small organic compounds: 1FSY AMP-C, 4EY2 NDM-1 and 1PZP TEM-1. Additional in silico molecular docking and prediction of ADMET properties were performed with SeeSAR (from BiosolveIT). The in vitro screening platform, using kinetics of β-lactamase inhibition with nitrocefin substrate, further validated the SBDD mediated discovery of novel small organic molecules exhibiting inhibitory constants, Ki, in the low uM-nM range and selectivity for Y-49 β lactamase.

Structure-based drug design (SBDD) and in silico pharmacophore screening approaches coupled with biochemical validation enabled the discovery of small organic molecules modulators of Y-49, TEM-1 and ampC beta lactamases

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.