Screening and Identification of Potential Inhibitors Against Udp-N Acetyl Glucosamine Enolpyruvyl Transferase(Mura) in Streptococcus Pneumonia: An Insilico Approach (original) (raw)
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Main aim of the current study was to discover novel inhibitors against Streptococcus pneumoniae MurF enzyme using analogue based drug design. Pharmacophore mapping and 3D-QSAR analysis was performed on some previously synthesized and evaluated sulfonamide derivatives which are known to be potent inhibitors of penicillin resistant Streptococcus pneumoniae MurF receptor. 3D-QSAR study based on the principle of alignment of pharmacophoric features was performed on the same set of inhibitors using the PHASE module of Schrodinger suite. A five point pharmacophore, ADHRR, with one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic group and two aromatic rings yielded a statistically significant 3D-QSAR model with 0.96 as R 2 value for three PLS components and good predictive correlation coefficients of Q 2 = 0.8084, F = 140.6 and Pearson-R = 0.9157 for the test set with nine compounds. Thus, indicating good predictive power of the pharmacophore based 3D-QSAR model.
2009
Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and about two million deaths are attributable to TB annually. The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. In this work, 3D structural model of Mtb-MurA enzyme has been developed, for the first time, by homology modeling and molecular dynamics simulation techniques. The model provided clear insight in its structure features, i.e. substrate binding pocket, and common docking site. Multiple sequence alignment and 3D structure model provided the putative substrate binding pocket of Mtb-MurA with respect to E.coli MurA. This analysis was helpful in identifying the binding sites and molecular function of the MurA homologue. Molecular docking study was performed on this 3D structural model, using different classes of inhibitors like fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic acid derivatives T6361, T6362 and the results showed that the 5sulfonoxyanthranilic acid derivatives is showed best interaction compared with other inhibitor, taking in to this we also design a new efficient analogs of T6361 and T6362 which are showed even better interaction with Mtb-MurA than the parental5-sulfonoxy-anthranilic acid derivatives. Further the comparative molecular electrostatic potential and cavity depth analysis of Mtb-MurA suggested several important differences in its substrate and inhibitor binding pocket. Such differences could be exploited in the future for designing of a more specific inhibitor for Mtb-MurA enzyme
Main aim of the current study was to discover novel inhibitors against Streptococcus pneumoniae MurF enzyme using analogue based drug design. Pharmacophore mapping and 3D-QSAR analysis was performed on some previously synthesized and evaluated sulfonamide derivatives which are known to be potent inhibitors of penicillin resistant Streptococcus pneumoniae MurF receptor. 3D-QSAR study based on the principle of alignment of pharmacophoric features was performed on the same set of inhibitors using the PHASE module of Schrodinger suite. A five point pharmacophore, ADHRR, with one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic group and two aromatic rings yielded a statistically significant 3D-QSAR model with 0.96 as R2 value for three PLS components and good predictive correlation coefficients of Q2 = 0.8084, F = 140.6 and Pearson-R = 0.9157 for the test set with nine compounds. Thus, indicating good predictive power of the pharmacophore based 3D-QSAR model.
Journal of Chemical Information and Modeling, 2007
The biosynthetic pathway for formation of the bacterial cell wall (peptidoglycan) presents an attractive target for intervention. This is exploited by many of the clinically useful antibiotics, which inhibit enzymes involved in the later stages of peptidoglycan synthesis. MurF is one of the four amide bond-forming enzymes (d-alanyl-d-alanine ligating enzyme) that catalyzes the ATP-dependent formation of UDP-MurNAc-tripeptide. In the present study, several MurF inhibitors were docked into the active site of MurF to explore their binding modes and also to gain an insight into the crucial ligand-receptor interactions at the molecular level. The final selection of the "bioactive" conformation of every ligand was influenced by consensus scoring in which various independent scoring functions such as GoldScore, ChemScore, HINT score and X-CScore were employed. Subsequently, 3D-QSAR studies using comparative molecular field analysis (CoMFA) and the new approach comparative residue interaction analysis (CoRIA) have been carried out on the enzyme-inhibitor complexes obtained by docking and postscoring analysis. Finally, new inhibitors have been designed using the de novo approach of Ludi, and the activities of the most promising hits have been predicted with the CoMFA and CoRIA models.
Journal of Biological Chemistry, 2000
The bifunctional bacterial enzyme N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmU) catalyzes the two-step formation of UDP-GlcNAc, a fundamental precursor in bacterial cell wall biosynthesis. With the emergence of new resistance mechanisms against -lactam and glycopeptide antibiotics, the biosynthetic pathway of UDP-GlcNAc represents an attractive target for drug design of new antibacterial agents. The crystal structures of Streptococcus pneumoniae GlmU in unbound form, in complex with acetyl-coenzyme A (AcCoA) and in complex with both AcCoA and the end product UDP-GlcNAc, have been determined and refined to 2.3, 2.5, and 1.75 Å, respectively. The S. pneumoniae GlmU molecule is organized in two separate domains connected via a long ␣-helical linker and associates as a trimer, with the 50-Å-long left-handed -helix (LH) Cterminal domains packed against each other in a parallel fashion and the C-terminal region extended far away from the LH core and exchanged with the -helix from a neighboring subunit in the trimer. AcCoA binding induces the formation of a long and narrow tunnel, enclosed between two adjacent LH domains and the interchanged C-terminal region of the third subunit, giving rise to an original active site architecture at the junction of three subunits. GlmU catalyzes acetyltransfer from acetyl-coenzyme A (Ac-CoA) 1 to glucosamine-1-P with release of GlcNAc-1-P, and subsequently uridyltransfer from UTP to GlcNAc-1-P in the presence of Mg 2ϩ , yielding PPi and the nucleotide-activated precursor sugar UDP-GlcNAc (1) (see Fig. 1A). UDP-GlcNAc is
Informatics in Medicine Unlocked, 2018
Experimental corrosion study was often high-cost and time-consuming since large-scale trial experiments were carried out. An In-silico method was used to study the inhibition performance of twenty-five amino acids and related compounds. Density Functional Theory (B3LYP/6-31G*) quantum chemical calculation method was used to find the optimized geometry of the studied inhibitors. Additionally, a linear quantitative structure-activity relationship (QSAR) model was built by Genetic Function Approximation (GFA) method to run the regression analysis and establish correlations between different types of descriptors and the measured corrosion inhibition efficiencies which was used to predict the corrosion inhibition efficiencies of the studied inhibitors. The prediction of corrosion efficiencies of these inhibitors nicely matched the experimental measurements. The correlation parameters obtained are R train 2 = 0.98, R adjusted 2 = 0.98, Q LOO 2 = 0.97, R test 2 =0.86. This indicates that the model was excellent on verifying with internal and external validation parameters. The affection of acidic solution was considered in molecular dynamics simulation and the calculated adsorption energies for most of the inhibitors is ˃100 kcal mol −1 suggesting chemisorptive interactions.
The bacterial cell wall represents an attractive target site for antibiotic research as it is a fundamental structure for bacterial survival. The enzyme MurA (UDP-Nacetylglucosamine enolpyruvyl transferase, accomplishes an initial step in the cytoplasmic biosynthesis of peptidoglycan precursor molecules. It catalyzes the transfer reaction of phosphoenolypyruvate (PEP) to the 3'hydroxyl group of UDP-N-acetyl glucosamine (UNAG) generating enolpyruvyl-UDPN-acetyl glucosamine (EP-UNAG) and inorganic phosphate. The broadspectrum antibiotic fosfomycinto date still the only known MurA inhibitor with clinical relevance -acts as an analogue of the substrate PEP by irreversible alkylation of the Cys115 thiol group .The MurA-dependent metabolites are of vital importance for bacteria, and the enzyme is therefore in the focus of anti bacterial drug discovery.