Structure-based Druggability Assessment of Anti-virulence Targets from Pseudomonas 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.

Synthesis and biological evaluation of thiazolidinedione derivatives with high ligand efficiency to P. aeruginosa PhzS

“…According to Ni and co-workers (2019), 71 targeting enzymes from the pyocyanin biosynthesis pathway is a valid and underexplored strategy. In accordance with this standpoint of view, it has been proposed that PaPhzS is a druggable target 28 and we have shown that thiazolidine-2,4-dione derivatives, bearing a dihydroquinazoline ring at the para position of the benzylidene ring, have a micromolar affinity to PhzS from P. aeruginosa and reduce pyocyanin production without a significant impact on the cell growth rate 11 . The most promising compound (Figure 1(A)) might be employed for hit-to-lead optimisation efforts, but a careful analysis of its ligand efficiency argues otherwise.…”

“…In order to overcome this dilemma, antivirulence drugs, which aim at 'disarming' the pathogens instead of killing them, have been pursued [18][19][20][21] . In contrast to previous studies that focus on quorum sensing modulation [22][23][24][25] , in this work we target enzymes from the pyocyanin (PYO) biosynthesis pathway in P. aeruginosa, a Gramnegative bacillus with high degree of resistance to available drugs 26 , in particular PhzS, an enzyme that catalyses the last step of the PYO biosynthesis, because A) genetic validation (phzs gene knockout) suggests that this protein is crucial for P. aeruginosa infection progression 27 ; B) in silico tools predict this target to be druggable 28 ; C) the reaction catalysed by PhzS is NADH-dependent 29,30 . This last feature prompted the analysis of thiazolidine-2,4dione derivatives that might mimic the interaction profile of the purine ring from NADH.…”

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“…One popular approach is to design small-molecule enzyme inhibitors for critical pathways of microorganisms such as LPS, peptidoglycan, and quorum sensing [28]. In addition to traditional methods, genomics or proteomicsbased in-silico strategies enable to search potential druggable candidates for these small-molecule inhibitors in a fast manner [29][30][31]. Therefore, the cytoplasmic proteins of H. hepaticus were analyzed to reveal the enzymes that have a role in vital metabolic pathways that can serve as promising drug targets.…”

In Silico Methods for Identification of Potential Active Sites of Therapeutic Targets

“…When the proteins of interest are closely related homologs, particularly with a highly conserved sequence (e.g., >70% sequence identity), they tend to bind to chemically related ligands and catalyze similar reactions. Knowledge of the ligand/inhibitor of the related family member is likely to be useful for the design of the ligand/inhibitor of the target protein [ 53 ]. Reliable information on the target and ligand in terms of druggability can be obtained when information on homologs or family members of known targets and ligands can be found in databases, especially when these proteins have been subjected to clinical trials [ 52 ].…”