Selective DNA Gyrase Inhibitors: Multi-Target in Silico Profiling with 3D-Pharmacophores

Abstract

(1) Background: DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors against closely related human ATP-binding enzymes should be evaluated early in development to avoid off-target binding to homologous binding domains. (2) Methods: To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase IIα (TopoII), and the Hsp90 N-terminal domain (NTD) to be used in in silico activity profiling paradigms to identify molecules selective for GyrB over TopoII and Hsp90, as starting points for hit expansion and lead optimization. (3) Results: The models were used to profile highly active GyrB, TopoII, and Hsp90 inhibitors. Selected compounds were tested in in vitro assays. GyrB inhibitors 1 and 2 were inactive against TopoII and Hsp90, while 3 and 4, potent Hsp90 inhibitors, displayed no inhibition of GyrB and TopoII, and TopoII inhibitors 5 and 6 were inactive at GyrB and Hsp90. (4) Conclusions: The results provide a proof of concept for the use of target activity profiling methods to identify selective starting points for hit and lead identification.

In Silico Discovery and Optimisation of a Novel Structural Class of Hsp90 C-Terminal Domain Inhibitors

“…Representative compound 7l inhibited Hsp90-dependent luciferase refolding ( Supporting information, Figure S31 ), demonstrating that analogues of the virtual hit TVS-23 inhibit Hsp90. Next, we performed an in silico screening using a set of ligand-based pharmacophore models for the identification of Hsp90 NTD inhibitors [ 55 ], which resulted in no hits. Because the observed SAR is consistent with the hypothesis for the binding to the proposed Hsp90 CTD binding site and TVS-23 and its analogues do not have the necessary features of Hsp90 NTD inhibitors, we believe that they bind to the Hsp90 CTD.…”

Heat Shock Protein 90 (HSP90) Inhibitors as Anticancer Medicines: A Review on the Computer-Aided Drug Discovery Approaches over the Past Five Years

“…The best linear model's R correlation coefficient was 0.89 and 0.11 and resulted in the development of two nonlinear models [ 158 ]. In another study, Tomašič et al applied the three-dimensional pharmacophore profiling on selective DNA gyrase and HSP90 inhibitors [ 159 ]. The authors designed selective three-dimensional pharmacophore systems for GyrB, human topoisomerase II α (TopoII), and the HSP90 N-terminal domain (NTD) used as starting points for hit expansion and lead optimisation.…”

“…In vitro studies against E. coli DNA gyrase and human TopoII validated the prediction of selective HSP90 NTD inhibition for 3 and 4, which was also confirmed in in vitro assays against E. coli DNA gyrase and human TopoII. It was confirmed that designing three-dimensional chemical parameter-based pharmacophore models are useful instruments for predicting the activity and selectivity of known and novel HSP90 and GyrB inhibitors [ 159 ].…”

Synthesis and pharmacological evaluation of 1,3-diaryl substituted pyrazole based (thio)urea derivatives as potent antimicrobial agents against multi-drug resistant Staphylococcus aureus and Mycobacterium tuberculosis

“…Similarly, many reported scaffolds with a urea moiety do act as potent DNA gyrase inhibitors embodied with antibacterial properties. 49–52 DNA gyrase is a type II topoisomerase that is a proven validated target in bacteria for the discovery of new antibacterial agents. 53…”

“…Similarly, many reported scaffolds with a urea moiety do act as potent DNA gyrase inhibitors embodied with antibacterial properties. [49][50][51][52] DNA gyrase is a type II topoisomerase that is a proven validated target in bacteria for the discovery of new antibacterial agents. Considering the promising antimicrobial profile and the common target of the pyrazole scaffold and (thio)urea functionality, the present study aims to combine both moieties through molecular hybridization Fig.…”