Designing of potential inhibitors against Staphylococcus aureus sortase A: Combined analogue and structure based approach with in vitro validation (original) (raw)
Related papers
Combined pharmacophore and 3D-QSAR study on a series of Staphylococcus aureus Sortase A inhibitors
Chemical biology & drug design, 2012
Methicillin resistant Staphylococcus aureus has become a major health concern and it requires new therapeutic agents. Staphylococcus aureus Sortase A enzyme contributes in adherence of bacteria with the cell wall of host cell; consequently, inhibition of S. aureus Sortase A by small molecules could be employed as potential antibacterial agents against methicillin resistant S. aureus. Current study focused on the identification of 3D pharmacophoric features within a series of rhodanine, pyridazinone, and pyrazolethione analogs as S. aureus Sortase A inhibitors. Pharmacophore model was constructed employing representative molecules using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database. The identified pharmacophoric points were then utilized to create alignment hypothesis for three-dimensional quantitative structure-activity relationships. Outcome of comparative molecular field analysis and comparative molecular similarity indices analysis experiments were in good agreement (comparative molecular field analysis: q 2 = 0.562 and r 2 = 0.995, comparative molecular similarity indices analysis: q 2 = 0.549 and r 2 = 0.978) and capable of explaining the variance in biological activities coherently with respect to the structural features of compounds. The results were also found in concurrence with the outcome of pharmacophoric features.
European Journal of Medicinal Chemistry, 2010
Synthetic methods have been developed for lead Sortase A inhibitors identified from previous studies. Several derivatives of the lead inhibitor were synthesized to derive preliminary structure activity relationships (SAR). Different regions of the lead inhibitor that are critical for the enzyme activity have been determined by systematic SAR studies. The E stereochemistry of the lead compound was found to be critical for its activity. Replacement of the E double bond with Z double bond or a rigid triple bond reduced the enzyme inhibitory activity in most cases. Reduction of the double bond to a C–C single bond resulted in complete loss of activity. Amide carbonyl and NH groups were also found to be crucial for the activity of this class of inhibitors, as well. The morpholine ring oxygen atom was also found to be an important factor for the activity of the lead inhibitor. Preliminary SAR studies led to the identification of compounds with improved enzyme inhibition. The most active compound was found to have an IC50 value of 58 μM against the enzyme.Synthesis and structure activity relationship studies of a lead structural template of Staphylococcus aureus Sortase A inhibitor are described.
Chemical Data Collections, 2018
Briefly describe the contentof thisdata article. If data is supplied with the data article, please explicitly state this or indicate the reference number and repository name for the data stored elsewhere. If this article is related to a published full research article, please also directly mention the article in the abstract] Novel molecules were designed against Staphylococcus aureus sortase A, an imperative and vital target involved in the bacterial virulence. Structure guided de novo designing was performed using different chemical fragments. These fragments were extended based on the requirements of the binding cavity. All the compounds in its binding orientation has formed good interaction network with amino acids HIS 120 and ARG 197. Molecules designed contain indole-chroman and indolin-chroman moieties and their docking scores were ranging from-6.92 to-5.67. Designed molecules were selected for synthesis and tested in vitro against Staphylococcus aureus sortase A using Fluorescence resonance energy transfer assay. The highest active molecule KK4 ((Z)-3-((5-nitro-1H-indol-3-yl) methylene) chroman-2,4-dione)
International Journal of Zoological Investigations
This study was performed to examine molecular docking of newly synthesised thiazolidinone compounds and discover potential InhA inhibitors. MIC screening produced thiazolidinone derivatives for Staphylococcus aureus illness. KBr pellet FT-IR spectra were collected on a Thermo Nicolet AVATAR-330 spectrometer. Bruker obtained 400 MHz 1H spectra of all chemicals in DMSO-d6. Five 4 thiazolidinone derivatives:4-(4-oxo-2-phenylthiazolidin-3yl)amino)benzyl)oxazolidin-2-one(8), ((2-(4 chlorophenyl)-4oxothiazolidin-3yl)amino)benzyl)- oxazolidin-2-one(9), ((2-(4-fluorophenyl)-4-oxothiazolidin-3 yl)amino)benzyl)oxazolidin-2-one(10), 4-(4-((4-oxo2-(p-tolyl)thiazolidin-3yl)amino)benzyl)oxazolidin-2-one(11) and 4-(4-((2-(4 methoxyphenyl)-4-oxothiazolidin3yl)amino)benzyl)oxazolidin-2-one(12) docked due to its vast biological usefulness. Molecular docking, ADMET, TOPKAT Toxicity, and molecular dynamic simulation were used to estimate drug-likeness for 1QG6. MIC screening of synthesised thiazolidino...
The Journal of Antibiotics
Staphylococcus aureus is one of the most dangerous pathogens commonly associated with high levels of morbidity and mortality. Sortase A is considered as a promising molecular target for the development of antistaphylococcal agents. Using hybrid virtual screening approach and FRET analysis, we have identified five compounds able to decrease the activity of sortase A by more than 50% at the concentration of 200 µM. The most promising compound was 2-(2-amino-3-chlorobenzoylamino)-benzoic acid which was able to inhibit S. aureus sortase A at the IC 50 value of 59.7 µM. This compound was selective toward sortase A compared to other four cysteine proteasescathepsin L, cathepsin B, rhodesain, and the SARS-CoV2 main protease. Microscale thermophoresis experiments confirmed that this compound bound sortase A with K D value of 189 µM. Antibacterial and antibiofilm assays also confirmed high specificity of the hit compound against two standard and three wild-type, S. aureus hospital infection isolates. The effect of the compound on biofilms produced by two S. aureus ATCC strains was also observed suggesting that the compound reduced biofilm formation by changing the biofilm structure and thickness.
Malaysian Journal of Analytical Science, 2019
The emergence of antibiotic resistance against bacterial strains has attracted great interest in the discovery and development of new antibacterial agents. Thiazole derivatives have been widely used in the biological as well as pharmacological fields and their efficiency as pharmaceutical drugs are well established. In this study, a series of thiazole derivatives were synthesized in reaction between 3-chloroacetyl acetone and ammonium thiocyanate followed by incorporating selected amines in one-pot synthesis manner. The compounds were structurally characterized by Fourier Transform Infrared (FTIR), Proton Nuclear Magnetic Resonance (1 H NMR), Ultraviolet-Visible (UV-Vis) and Gas Chromatography-Mass Spectrometry (GC-MS). Their antibacterial properties were screened using disc diffusion technique against selected Gram-positive (Bacillus cereus and Staphylococcus epidermidis) as well as Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) with T3 exhibited the most potent antibacterial activity. Molecular docking studies were also performed against Glucosamine-6-phosphate (GlcN-6-P) synthase which is known as the essential building block of most bacteria. The docking result displayed that T3 exhibited the minimum binding energy of-7.09 kcal mol-1 as compared to T1 and T2 with-6.49 and-6.76 kcal mol-1 , respectively which is in agreement with antibacterial result. The output of this preliminary study will contribute in structural enhancement in drug discovery.
Structural Analysis of Sortase A Inhibitors
Molecules, 2016
Bacterial sortases are cysteine transpeptidases that regulate the covalent linkage of several surface protein virulence factors in Gram-positive bacteria. Virulence factors play significant roles in adhesion, invasion of host tissues, biofilm formation and immune evasion, mediating the bacterial pathogenesis and infectivity. Therefore, sortases are emerging as important targets for the design of new anti-infective agents. We employed a computational study, based on structure derived descriptors and molecular fingerprints, in order to develop simple classification methods which could allow predicting low active or high active SrtA inhibitors. Our results indicate that a highly active SrtA inhibitor has a molecular weight ranging between 180 and 600, contains one up to four nitrogen atoms, up to three oxygen atoms and under 18 hydrogen atoms. Also the hydrogen acceptor number and the molecular flexibility, as assessed by the number of rotatable bounds, have emerged as the most relevant descriptors for SrtA affinity. The Bemis-Murcko scaffolding revealed favoured scaffolds as containing at least two ring structures bonded directly or merged in a condensed cycle. This data represent a valuable tool for identifying new potent SrtA inhibitors, potential anti-virulence agents targeted against Gram-positive bacteria, including multiresistant strains.
Molecular Docking and Screening Studies of New Natural Sortase A Inhibitors
International journal of molecular sciences, 2017
To date, multi-drug resistant bacteria represent an increasing health threat, with a high impact on mortality, morbidity, and health costs on a global scale. The ability of bacteria to rapidly and permanently acquire new virulence factors and drug-resistance elements requires the development of new antimicrobial agents and selection of new proper targets, such as sortase A. This specific bacterial target plays an important role in the virulence of many Gram-positive pathogens, and its inhibition should produce a mild evolutionary pressure which will not favor the development of resistance. A primary screening using a fluorescence resonance energy transfer assay was used to experimentally evaluate the inhibitory activity of several compounds on sortase A. Using molecular docking and structure-activity relationship analyses, several lead inhibitors were identified, which were further tested for antimicrobial activity using the well diffusion test and minimum inhibitory concentration. ...
2021
This work include several advanced molecular docking tools to study the interactions of our newly synthesized 1,3,4-thiadiazole derivatives in the active site of penicillin binding protein and DNA gyrase against Staphylococcus aureus, the enzymes targeted for antimicrobial agents. Results such as MolDock scores, binding energies, residue binding distances, etc. were identified and discussed in this present research. The molecules with best docking results were selected in order to calculate drug likeness and bioavailability using Molinspiration software. All the compounds obey Lipinski’s rule and its extension and showed drug likeness. The pharmacokinetic parameters study was done using the AdmetSAR to display ADME and toxicity properties of these antimicrobial.
Identification of novel inhibitors of bacterial surface enzyme Staphylococcus aureus Sortase A
Bioorganic & Medicinal Chemistry Letters, 2008
In-silico virtual screening of bacterial surface enzyme Staphylococcus aureus Sortase A against commercial compound libraries using FlexX software package has led to the identification of novel inhibitors. Inhibition of enzyme catalytic activity was determined by monitoring the steady state cleavage of a model peptide substrate. Preliminary structure activity relationship studies on the lead compound resulted in the identification of compounds with improved activity. The most active compound has an IC50 value of 58 μM against the enzyme.A novel class of inhibitors of Staphylococcus aureus Sortase A is discovered by in-silico virtual screening and structure activity relationship studies.