Title:Structure-based Druggability Assessment of Anti-virulence Targets from Pseudomonas aeruginosa
Volume: 20
Issue: 12
Author(s): Thamires Q. Froes, Regina L. Baldini, Sandor Vajda and Marcelo S. Castilho*
Affiliation:
- Programa de Pos-Graduacao em Biotecnologia da Universidade Estadual de Feira de Santana, Feira de Santana, BA,Brazil
Keywords:
Hotspot analysis, solvent mapping, PockDrug, druggability, antimicrobial-resistance, quorum sensing, pyocyanin,
P. aeruginosa.
Abstract: Antimicrobial Resistance (AMR) represents a serious threat to health and the global economy.
However, interest in antibacterial drug development has decreased substantially in recent decades.
Meanwhile, anti-virulence drug development has emerged as an attractive alternative to fight AMR. Although
several macromolecular targets have been explored for this goal, their druggability is a vital
piece of information that has been overlooked. This review explores this subject by showing how structure-
based freely available in silico tools, such as PockDrug and FTMap, might be useful for designing
novel inhibitors of the pyocyanin biosynthesis pathway and improving the potency/selectivity of compounds
that target the Pseudomonas aeruginosa quorum sensing mechanism. The information provided
by hotspot analysis, along with binding site features, reveals novel druggable targets (PhzA and PhzS)
that remain largely unexplored. However, it also highlights that in silico druggability prediction tools
have several limitations that might be overcome in the near future. Meanwhile, anti-virulence drug targets
should be assessed by complementary methods, such as the combined use of FTMap/PockDrug,
once the consensus druggability classification reduces the risk of wasting resources on undruggable proteins.
