Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand–based drug design

Magalhães, Joana; Franko, Nina; Annunziato, Giannamaria; Welch, Martin; Dolan, Stephen K.; Bruno, Agostino; Mozzarelli, Andrea; Armao, Stefano; Jirgensons, Aigars; Pieroni, Marco; Costantino, Gabriele; Campanini, Barbara

doi:10.1080/14756366.2018.1512596

Cited by 18 publications

(17 citation statements)

References 42 publications

(47 reference statements)

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“…Cysteine metabolism (i.e., de novo biosynthesis and degradation) [17], is intimately connected with many bacterial functions relevant to infection, such as resistance to oxidative stress and resistance to antibiotics [18,19,20,21,22], biofilm formation [23], and toxin activation [24,25]. For this reason, this metabolic pathway has received much attention in the last ten years as a potential target for the development of antibiotics or antibiotic enhancers [17,26,27,28,29,30,31,32,33,34,35,36,37,38]. Cysteine biosynthesis in bacteria is performed through eight enzymes plus several permeases [17] (Figure 1A) that allow entry of sulfate/thiosulfate inside the cell.…”

Section: Introductionmentioning

confidence: 99%

Combination of SAXS and Protein Painting Discloses the Three-Dimensional Organization of the Bacterial Cysteine Synthase Complex, a Potential Target for Enhancers of Antibiotic Action

Rosa

Marchetti

Paredi

et al. 2019

IJMS

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The formation of multienzymatic complexes allows for the fine tuning of many aspects of enzymatic functions, such as efficiency, localization, stability, and moonlighting. Here, we investigated, in solution, the structure of bacterial cysteine synthase (CS) complex. CS is formed by serine acetyltransferase (CysE) and O-acetylserine sulfhydrylase isozyme A (CysK), the enzymes that catalyze the last two steps of cysteine biosynthesis in bacteria. CysK and CysE have been proposed as potential targets for antibiotics, since cysteine and related metabolites are intimately linked to protection of bacterial cells against redox damage and to antibiotic resistance. We applied a combined approach of small-angle X-ray scattering (SAXS) spectroscopy and protein painting to obtain a model for the solution structure of CS. Protein painting allowed the identification of protein–protein interaction hotspots that were then used as constrains to model the CS quaternary assembly inside the SAXS envelope. We demonstrate that the active site entrance of CysK is involved in complex formation, as suggested by site-directed mutagenesis and functional studies. Furthermore, complex formation involves a conformational change in one CysK subunit that is likely transmitted through the dimer interface to the other subunit, with a regulatory effect. Finally, SAXS data indicate that only one active site of CysK is involved in direct interaction with CysE and unambiguously unveil the quaternary arrangement of CS.

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Section: Introductionmentioning

confidence: 99%

Combination of SAXS and Protein Painting Discloses the Three-Dimensional Organization of the Bacterial Cysteine Synthase Complex, a Potential Target for Enhancers of Antibiotic Action

Rosa

Marchetti

Paredi

et al. 2019

IJMS

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“…In 2016, Pieroni et al [115,116], starting from the evidence that SAT competitively inhibits OASS-A, developed a rational design of the first sulfydrylase inhibitors based on the structural features of the OASS–SAT interaction. Taking into account the data from their previous studies [117], and combining computational [118,119] and spectroscopic approaches, such as saturation transfer difference (STD) and nuclear magnetic resonance (NMR), they rationally designed and synthesized a series of 2-phenylcyclopropane carboxylic acid derivatives tested against both isoforms of St -OASS [120]. Indeed, they demonstrated that the compounds binding to the enzyme active sites efficiently inhibit both OASS-A and B isoforms by competing with SAT.…”

Section: Targeting Antivirulence Factorsmentioning

confidence: 99%

Strategies to Overcome Antimicrobial Resistance (AMR) Making Use of Non-Essential Target Inhibitors: A Review

Annunziato

2019

IJMS

180

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Antibiotics have always been considered as one of the most relevant discoveries of the twentieth century. Unfortunately, the dawn of the antibiotic era has sadly corresponded to the rise of the phenomenon of antimicrobial resistance (AMR), which is a natural process whereby microbes evolve in such a way to withstand the action of drugs. In this context, the identification of new potential antimicrobial targets and/or the identification of new chemical entities as antimicrobial drugs are in great demand. To date, among the many possible approaches used to deal with antibiotic resistance is the use of antibiotic adjuvants that hit bacterial non-essential targets. In this review, the author focuses on the discovery of antibiotic adjuvants and on new tools to study and reduce the prevalence of resistant bacterial infections.

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“…Scaffold hopping is a powerful and promising strategy for drug discovery 34 . It has been extensively used for the design of structurally novel bioactive molecules [35][36][37][38] , which generally incorporates ring opening, ring closure, heterocycle replacement, and shape/topology-based scaffold hopping 39,40 . Herein, we applied the heterocycle replacement and shape-based scaffold hopping strategy towards PFI-1, a BRD inhibitor developed by Pfizer Worldwide R&D. First, we analysed the binding mode of PFI-1 binds to the BRD4 bromodomain.…”

Section: Design Of New Brd4 Inhibitors Containing a Coumarin Scaffoldmentioning

confidence: 99%

Discovery of novel coumarin derivatives as potent and orally bioavailable BRD4 inhibitors based on scaffold hopping

Zhang

Wang

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development.

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Discovery of novel fragments inhibiting O-acetylserine sulphhydrylase by combining scaffold hopping and ligand–based drug design

Cited by 18 publications

References 42 publications

Combination of SAXS and Protein Painting Discloses the Three-Dimensional Organization of the Bacterial Cysteine Synthase Complex, a Potential Target for Enhancers of Antibiotic Action

Combination of SAXS and Protein Painting Discloses the Three-Dimensional Organization of the Bacterial Cysteine Synthase Complex, a Potential Target for Enhancers of Antibiotic Action

Strategies to Overcome Antimicrobial Resistance (AMR) Making Use of Non-Essential Target Inhibitors: A Review

Discovery of novel coumarin derivatives as potent and orally bioavailable BRD4 inhibitors based on scaffold hopping

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