Discovery of New Inhibitors of Resistant <i>Streptococcus pneumoniae</i> Penicillin Binding Protein (PBP) 2x by Structure-Based Virtual Screening

Miguet, Laurence; Zervosen, Astrid; Gerards, Thomas; Pasha, Farhan Ahmad; Luxen, André; Distèche-Nguyen, Martine; Thomas, Aline

doi:10.1021/jm900625q

Cited by 22 publications

(12 citation statements)

References 58 publications

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“…The application of molecular docking in drug design is more mature. Miguet et al [8] screened out 55 potential inhibitors of penicillin binding proteins from 2.6×10 5 compounds by molecular docking and the results were in good agreement with the experimental report. Three kinds of new and effective inhibitors were obtained.…”

Section: Introductionsupporting

confidence: 58%

Virtual substrates screening model of triacylglycerol lipase from Bacillus thermocatenulanatus

Fang

2011

Wuhan Univ. J. Nat. Sci.

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A reliable 3-D structure of Triacylglycerol lipase from Bacillus thermocatenulanatus was constructed by homology modeling. Under molecular dynamics simulation, it was refined and checked. The model was further used as a receptor to search binding sites and carry out flexible docking with a range of substrates, whose enzyme activities were already measured. By inputting a series of docking results, virtual substrates screening models were established and assessed. Monadic nonlinear solution demanded less data but was weak in fitting enzyme activity data with little difference; its mean absolute percentage error (MAPE) of regression was 0.67 and mean square error (MSE) was 1.73 U/mg. Both quadratic stepwise regression and BP neural network were good in regression and prediction; however, more data were required. In the cross-validation of 12 groups, overall MAPE of regression and prediction for the former were 0.18 and 0.49, while the latter was 0.55 and 0.36. MSE values for these two methods were 0.95 and 1.20 U/mg, respectively. Therefore, monadic nonlinear regression model can be used as a preliminary screening one; quadratic stepwise regression and BP neural network approach can be applied to precise screening.Triacylglycerol lipase from bacillus thermocatenulanatus (BTL2) belongs to thermal stable lipases. It can hydrolyze saturated and unsaturated esters of different chain lengths into alcohols and acids. Because it is derived from thermophilic microorganism, its high-temperature endurance is remarkable, the optimal temperature could be as high as 60 ℃. The lipase has attracted special attention for its various potential industrial applications [1] . The gene of BTL2 has been cloned and expressed in E.coli [2] . Liu et al [3] determined activities of several substrates to this enzyme. The experimental data are vital for the certification of virtual screening model. Molecular docking [4] is based on the lock and key principle to simulate the interactions between small molecules (ligand) and biological macromolecules (receptor). Wein et al [5] got the 3-D model of γ-aminobutyric acid (GABA) transporter protein hGAT-1 by homology modeling, for which 12 compounds were applied flexible docking to hGAT-1 and sorted by docking scores, the order of most ligands was consistent with the experimental results. Chu et al [6] employed the N-acetylneuraminate lyase model to dock with two substrates. It showed higher enzyme activity on sialic acid, which was validated by experimental data [7] . The application of molecular docking in drug design is more mature. Miguet et al [8] screened out 55 potential inhibitors of penicillin binding proteins from 2.6×10 5 compounds by molecular docking and the results were in good agreement with the experimental report. Three kinds of new and effective inhibitors

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Section: Introductionsupporting

confidence: 58%

Virtual substrates screening model of triacylglycerol lipase from Bacillus thermocatenulanatus

Fang

2011

Wuhan Univ. J. Nat. Sci.

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“…Some approaches have sought to adapt the β-lactam moiety by, for instance, incorporating elements of the peptide substrates onto one of the R1 or R2 side chains [37], [38], [39], while others have synthesized compounds that mimic the tetrahedral intermediates of the reaction, including phosphonates and boronates [40], [41], [42], [43]. Given the wealth of structural information for several clinically important PBPs, in silico docking has also been employed in some systems [44]. To contribute to this effort, we have developed a high-throughput assay for PBPs that measures the fluorescence polarization (FP) of Bocillin-FL [27] and used it to screen for potential inhibitors of N. gonorrhoeae PBP 2 from a library of 50,080 compounds.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening for Novel Inhibitors of Neisseria gonorrhoeae Penicillin-Binding Protein 2

et al. 2012

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The increasing prevalence of N. gonorrhoeae strains exhibiting decreased susceptibility to third-generation cephalosporins and the recent isolation of two distinct strains with high-level resistance to cefixime or ceftriaxone heralds the possible demise of β-lactam antibiotics as effective treatments for gonorrhea. To identify new compounds that inhibit penicillin-binding proteins (PBPs), which are proven targets for β-lactam antibiotics, we developed a high-throughput assay that uses fluorescence polarization (FP) to distinguish the fluorescent penicillin, Bocillin-FL, in free or PBP-bound form. This assay was used to screen a 50,000 compound library for potential inhibitors of N. gonorrhoeae PBP 2, and 32 compounds were identified that exhibited >50% inhibition of Bocillin-FL binding to PBP 2. These included a cephalosporin that provided validation of the assay. After elimination of compounds that failed to exhibit concentration-dependent inhibition, the antimicrobial activity of the remaining 24 was tested. Of these, 7 showed antimicrobial activity against susceptible and penicillin- or cephalosporin-resistant strains of N. gonorrhoeae. In molecular docking simulations using the crystal structure of PBP 2, two of these inhibitors docked into the active site of the enzyme and each mediate interactions with the active site serine nucleophile. This study demonstrates the validity of a FP-based assay to find novel inhibitors of PBPs and paves the way for more comprehensive high-throughput screening against highly resistant strains of N. gonorrhoeae. It also provides a set of lead compounds for optimization of anti-gonococcal agents.

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“… Left: active site region of the acyl‐enzyme complex formed between ceftobiprole and S. aureus PBP2a 128 . Right: structure of ceftobiprole.…”

Section: Antibacterialsmentioning

confidence: 99%

“…Recently, Miguet et al 128 . used a hierarchical VS procedure using the NCI database containing approximately 260,000 compounds to find novel inhibitors of a resistant strain of PBP2x from Streptococcus pneumoniae ( sp PBP2x).…”

Section: Antibacterialsmentioning

confidence: 99%

Structure‐based design of anti‐infectives

Agarwal

Fishwick

2010

Annals of the New York Academy of Sciences

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Infectious diseases, caused by bacteria, viruses, fungi, protozoa, or parasites are among the leading causes of death worldwide. The efficacy of all current anti-infectives is threatened by the spread of drug resistance factors, with some already made ineffective, and, as a result, there is a pressing need for a new pipeline of robust anti-infective drugs. In silico approaches, such as virtual high throughput screening and de novo structure-based rational drug design, have been established as powerful tools in drug discovery. In this review, we explore the exciting opportunities for antimalarial, antiviral, and antibacterial drug discovery arising from the new paradigm of structure-based drug design.

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Discovery of New Inhibitors of Resistant Streptococcus pneumoniae Penicillin Binding Protein (PBP) 2x by Structure-Based Virtual Screening

Cited by 22 publications

References 58 publications

Virtual substrates screening model of triacylglycerol lipase from Bacillus thermocatenulanatus

Virtual substrates screening model of triacylglycerol lipase from Bacillus thermocatenulanatus

High-Throughput Screening for Novel Inhibitors of Neisseria gonorrhoeae Penicillin-Binding Protein 2

Structure‐based design of anti‐infectives

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