Development and validation of a multi-level computational protocol for Drug Re-purposing in the treatment of Bacterial Infections

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes acute and chronic infections that are very difficult to eradicate due to acquired drug resistance and since it can also be organized in structured microbial communities forming a biofilm.

Biofilms are structured microbial communities of surface-attached cells embedded in a self-produced matrix of extracellular polymeric substances (EPS) that can be formed in a variety of biological and industrial surfaces. Controlling biofilm formation and development might be the key to hinder bacterial growth without leading to acquired drug resistance.

A biofilms structural database was created to quickly assess all the structural information on different protein structures involved in biofilm formation, development, and virulence available.

Here we report the optimization of a methodology using docking and virtual screening to identify novel clinical uses for already approved drugs. PqsD and PqsR molecular structures were selected as targets due to their crucial role in the formation and development of biofilms.

The FDA approved subset of the ZINC database was screened after careful validation of the Virtual Screening protocol. Subsequently, molecular dynamics and free energy calculation methods were performed in the top 15 results of each target, to further validate the results, calculate the binding free energy, and have a better understanding of the protein-ligand interactions established.