Structure-based druggability assessment of anti-virulence targets from Pseudomonas aeruginosa

(E-pub Abstract Ahead of Print)

Author(s): Thamires Quadros Froes, Regina Lúcia Baldini, Sandor Vajda, Marcelo Santos Castilho*.

Journal Name: Current Protein & Peptide Science

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Antimicrobial resistance (AMR) represents a serious threat to health and world economy. However, the interest in antibacterial drug development decreased significantly in the last decades. Meanwhile, anti-virulence drug development has emerged as an attractive alternative to fight AMR. Despite the fact that several macromolecular targets have been explored for this goal, their druggability is a vital piece of information that has been overlooked. This review paper sheds some light on this subject by showing how structure-based freely available in silico tools, such as PockDrug and FTMap, might be useful to design novel inhibitors of the pyocyanin biosynthesis pathway as well as improve the potency/selectivity of compounds that target the P. aeruginosa quorum sensing mechanism. The information provided by hotspots analysis, along with binding site features reveals novel druggable targets (PhzA and PhzS) that remain largely unexplored. However, it also points out that in silico druggability prediction tools have several limitations that might be overcome in the near future. Meanwhile, the assessment of anti-virulence drug targets should be carried out by complementary methods, such as FTMap/PockDrug combination, once the consensus druggability classification reduces the chances of wasting money and time on undruggable proteins.

Keywords: Hotspot analysis, solvent mapping, PockDrug, druggability, antimicrobial-resistance, quorum sensing, pyocyanin, P. aeruginosa.

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(E-pub Abstract Ahead of Print)
DOI: 10.2174/1389203720666190417120758
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