scholarly journals DOCKING STUDIES FOR VARIOUS ANTIBACTERIAL BENZILATE DERIVATIVES

2017 ◽  
Vol 10 (4) ◽  
pp. 268
Author(s):  
Sudha Rajendran ◽  
Brindha Devi P ◽  
Charles C Kanakam ◽  
Nithya G
Keyword(s):  
Infectious Disease ◽  
Amino Acids ◽  
Mycobacterium Tuberculosis ◽  
Active Site ◽  
Docking Studies ◽  
Antibacterial Drug ◽  
Structure Activity ◽  
Docking Tool ◽  
Excretion Study ◽  
Benzilic Acid

Objectives: In this study, we have focused on discovering the leads for the enzyme targets of infectious disease tuberculosis. We employed computeraided drug design docking tool,to discover new leads for Mycobacterium tuberculosis (MTB).Methods: Five compounds were synthesized and they are made to dock into the active site of the enzyme; retrieved from protein data bank.Results: The docking studies and structure–activity relationship reveals that the compound 2’-chloro-4-methoxy-3nitro benzilic acid after threedifferent docking strategies reveals that the score was found to be higher compared with others(−5.568 kcal/mol).Conclusion: On the closer analysis of this molecule, the molecule showed stacking interaction and the compound has also found to be surrounded by non-polar amino acids, which makes this molecule potent toward antibacterial drug discovery.Keywords: Antibacterials, Docking, Absorption, Distribution, Metabolism and excretion study, Resistance.

scholarly journals IN SILICO STUDIES FOR VARIOUS ANTIBACTERIAL BENZIL AND ITS SUBSTITUTED ANALOGS

2017 ◽  
Vol 10 (12) ◽  
pp. 186
Author(s):  
Nithya G ◽  
Sudha R ◽  
Brindha Devi P ◽  
Charles C Kanakam
Keyword(s):  
Infectious Disease ◽  
Antibacterial Drug ◽  
Computer Aided Drug Design ◽  
Enzyme Active Site ◽  
Structure Activity ◽  
In Silico Studies ◽  
Docking Tool ◽  
Low Levels ◽  
New Compounds ◽  
New Discovery

Objective: The antibacterials have moved on to low levels by more challenges toward antibacterial discovery of drug over an earlier period of 30 years. The resistance pathogens such as Staphylococcus aureus, Mycobacterium tuberculosis (MTB), and Streptococcus pneumoniae are nowadays facing difficulty in effective treatment. This leads to the necessary for the new discovery of drugs for antibacterial activity. The foremost disease in the world among all the infectious disease is found to tuberculosis (TB) which causes high proportions of mortality. Hence, we have decided on identifying the leads for the target of enzymes of infectious disease TB.Methods: The new leads for MTB have been discovered using computer-aided drug design docking tool. The new compounds identified were made to dock into the enzyme active site retrieved from protein data bank.Results: After three different docking strategies, the score was found to be 4.558 kcal mol−1 for the compound 2’-chloro-4-methoxy-3-nitro benzyl in structure activity relationship and docking studies.Conclusion: The molecule shows valuable interactions and also it is found to be surrounded by non-polar amino acids. On further analyzing the compound it is found to be potent to antibacterial drug discovery.

Synthesis and antimicrobial activity of aryldiazenyl/arylhydrazono pyrazoles

2021 ◽  
Vol 45 (11-12) ◽  
pp. 1093-1099
Author(s):  
Abdulrhman Alsayari ◽  
Yahya I Asiri ◽  
Abdullatif Bin Muhsinah ◽  
Mohd. Zaheen Hassan
Keyword(s):  
Active Site ◽  
Phenyl Ring ◽  
Antimicrobial Agents ◽  
Inhibitory Concentration ◽  
Docking Studies ◽  
Considerable Effect ◽  
Design Synthesis ◽  
Structure Activity ◽  
Antimicrobial Evaluation

We report the design, synthesis, and in vitro antimicrobial evaluation of functionalized pyrazoles containing a hydrazono/diazenyl moiety. Among these newly synthesized derivatives, 4-[2-(4-chlorophenyl)hydrazono]-5-methyl-2-[2-(naphthalen-2-yloxy)acetyl]-2,4-dihydro-3 H-pyrazol-3-one is a promising antimicrobial agent against Staphylococcus aureus (minimum inhibitory concentration 0.19 μg mL−1). Structure–activity relationship studies reveal that the electronic environment on the distal phenyl ring has a considerable effect on the antimicrobial potential of the hybrid analogues. Molecular docking studies into the active site of S. aureus dihydrofolate reductase also prove the usefulness of hybridizing a pyrazole moiety with azo and hydrazo groups in the design of new antimicrobial agents.

scholarly journals Design and Synthesis of Various 5′-Deoxy-5′-(4-Substituted-1,2,3-Triazol-1-yl)-Uridine Analogues as Inhibitors of Mycobacterium tuberculosis Mur Ligases

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4953
Author(s):  
Vincent Hervin ◽  
Ritu Arora ◽  
Jyoti Rani ◽  
Srinivasan Ramchandran ◽  
Urmi Bajpai ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Active Site ◽  
Inhibitory Effect ◽  
Natural Substrate ◽  
Screening Assay ◽  
One Pot ◽  
Peptidoglycan Biosynthesis ◽  
Design And Synthesis ◽  
Structure Activity

The synthesis of hitherto unknown 5′-deoxy-5′-(4-substituted-1,2,3-triazol-1-yl)-uridine and its evaluation, through an one-pot screening assay, against MurA-F enzymes involved in Mycobacterium tuberculosis (Mtb), are described. Starting from UDP-N-acetylmuramic acid (UDP-MurNAc), the natural substrate involved in the peptidoglycan biosynthesis, our strategy was to substitute the diphosphate group of UDP-MurNAc by a 1,2,3-triazolo spacer under copper-catalyzed azide-alkyne cycloaddition conditions. The structure-activity relationship was discussed and among the 23 novel compounds developed, N-acetylglucosamine analogues 11c and 11e emerged as the best inhibitors against the Mtb MurA-F enzymes reconstruction pathway with an inhibitory effect of 56% and 50%, respectively, at 100 μM. Both compounds are selective inhibitors of Mtb MurE, the molecular docking and molecular dynamic simulation suggesting that 11c and 11e are occupying the active site of Mtb MurE ligase.

scholarly journals Biochemical and Structural Characterization of the Secreted Chorismate Mutase (Rv1885c) from Mycobacterium tuberculosis H37Rv: an *AroQ Enzyme Not Regulated by the Aromatic Amino Acids

2006 ◽  
Vol 188 (24) ◽  
pp. 8638-8648 ◽  
Author(s):  
Sook-Kyung Kim ◽  
Sathyavelu K. Reddy ◽  
Bryant C. Nelson ◽  
Gregory B. Vasquez ◽  
Andrew Davis ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mycobacterium Tuberculosis ◽  
Active Site ◽  
Signal Sequence ◽  
Aromatic Amino Acids ◽  
Helical Structure ◽  
Data Bank ◽  
Chorismate Mutase ◽  
Site Directed Mutagenesis ◽  
Single Chain

ABSTRACT The gene Rv1885c from the genome of Mycobacterium tuberculosis H37Rv encodes a monofunctional and secreted chorismate mutase (*MtCM) with a 33-amino-acid cleavable signal sequence; hence, it belongs to the *AroQ class of chorismate mutases. Consistent with the heterologously expressed *MtCM having periplasmic destination in Escherichia coli and the absence of a discrete periplasmic compartment in M. tuberculosis, we show here that *MtCM secretes into the culture filtrate of M. tuberculosis. *MtCM functions as a homodimer and exhibits a dimeric state of the protein at a concentration as low as 5 nM. *MtCM exhibits simple Michaelis-Menten kinetics with a Km of 0.5 ± 0.05 mM and a k cat of 60 s−1 per active site (at 37°C and pH 7.5). The crystal structure of *MtCM has been determined at 1.7 Å resolution (Protein Data Bank identifier 2F6L). The protein has an all alpha-helical structure, and the active site is formed within a single chain without any contribution from the second chain in the dimer. Analysis of the structure shows a novel fold topology for the protein with a topologically rearranged helix containing Arg134. We provide evidence by site-directed mutagenesis that the residues Arg49, Lys60, Arg72, Thr105, Glu109, and Arg134 constitute the catalytic site; the numbering of the residues includes the signal sequence. Our investigation on the effect of phenylalanine, tyrosine, and tryptophan on *MtCM shows that *MtCM is not regulated by the aromatic amino acids. Consistent with this observation, the X-ray structure of *MtCM does not have an allosteric regulatory site.

scholarly journals Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Catherine T. Chaton ◽  
Emily S. Rodriguez ◽  
Robert W. Reed ◽  
Jian Li ◽  
Cameron W. Kenner ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Active Site ◽  
Fungal Species ◽  
Biosynthesis Pathway ◽  
Methionine Biosynthesis ◽  
Structure Based Drug Design ◽  
High Degree ◽  
Homoserine Transacetylase ◽  
Host Metabolism

AbstractMycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts l-homoserine to O-acetyl-l-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

scholarly journals The Homology Modeling and Docking Investigation of Human Cathepsin B

2020 ◽  
Vol 10 (1) ◽  
pp. 26687
Author(s):  
Afshin Khara ◽  
Ehsan Jahangirian ◽  
Hossein Tarrahimofrad
Keyword(s):  
Amino Acids ◽  
Protease Inhibitors ◽  
Cystatin C ◽  
Active Site ◽  
Cathepsin B ◽  
Antigen Processing ◽  
3D Structure ◽  
Cysteine Proteases ◽  
Docking Studies ◽  
Alternative Methods

Background: Cathepsin B comprises a group of lysosomal cysteine proteases belonging to the Papain family; it has an intracellular function in the process of protein catabolism, antigen processing in the immune response, and Alzheimer’s disease. In cancers, cathepsin B interferes with autophagy and intracellular catabolism, and breaks down extracellular matrix, decreases protease inhibitors expression, and ultimately helps to accelerate metastasis, tumor malignancy, and reduce immune resistance. Methods: In this study, the 3D structure of cathepsin B was constructed using modeler and Iterative Threading ASSEmbly Refinement (I-TASSER), based on similarity to the crystallographic model of procathepsin B (1PBH). Then, the predicted cathepsin B model was evaluated using PROCHECK and PROSA for quality and reliability. Molecular studies suggested that the amino acids cysteine 108, histidine 189, and histidine 190 form the envelope of the active site of cathepsin B. The docking studies of cathepsin B was performed with protease inhibitors cystatin C, E-64 and leupeptin. Results: The lowest binding energy was related to the cathepsin B-E-64 complex. Accordingly, it was found that E64 interacts with the amino acid cysteine 108 of the active site of cathepsin B. Leupeptin made 2 hydrogen bonds with cathepsin B, but none with the active site of cathepsin amino acids. Cystatin C established a hydrogen bond with the arginine 18 of cathepsin B and made electrostatic bonds with aspartate 148 of cathepsin B. Conclusion: Therefore, the bioinformatics and docking studies of cathepsin B with its inhibitors could be used as reliable identification, treatment, and alternative methods for selecting the inhibitors and controllers of cancer progression.

scholarly journals Molecular Docking Studies of α-Pyrone Derivatives Isolated from Alternaria phragmospora as CRM1 Inhibitors

2020 ◽  
Author(s):  
Ahmed Metwaly ◽  
Ibrahim Eissa ◽  
Ahmad Mostafa
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Chromosome Region ◽  
Docking Study ◽  
Docking Studies ◽  
Molecular Docking Study ◽  
Chemically Modified ◽  
Structure Activity ◽  
Modes Of Interaction ◽  
Chromosome Region Maintenance

Some α-Pyrone derivatives isolated from Alternaria phragmospora fungus showed promising anti leukemic activities, while others were inactive. CRM1/XPO1 (chromosome region maintenance 1 protein, also called exportin1 or PO1 in humans) has been chosen as a target for antileukemic molecular docking study for those compounds to understand their modes of interaction and structure activity relationships. The results showed that two (2 and 4), out of six, natural α-Pyrone derivatives exhibited well-established interactions with the amino acids of the receptor, which was in agreement with the experimental anti-leukemic results of these compounds. Moreover, twenty hypothetical chemically modified α-Pyrone derivatives (7-27) have been designed. Compounds 7, 8, 22 and 24 showed more efficient docking properties than the previously considered natural compounds.

scholarly journals Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

2019 ◽  
Author(s):  
Catherine T. Chaton ◽  
Emily S. Rodriguez ◽  
Robert W. Reed ◽  
Jian Li ◽  
Cameron W. Kenner ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Mycobacterium Tuberculosis ◽  
Active Site ◽  
Fungal Species ◽  
Biosynthesis Pathway ◽  
Methionine Biosynthesis ◽  
Structure Based Drug Design ◽  
High Degree ◽  
Homoserine Transacetylase ◽  
Host Metabolism

AbstractMycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts L-homoserine to O-acetyl-L-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

scholarly journals PROTEASES ASSOCIATED WITH Mycobacterium tuberculosis INFECTION

2019 ◽  
Vol 48 (1) ◽  
pp. 1-12
Author(s):  
Rayanny Gomes de Andrade ◽  
Ana Paula Junqueira-Kipnis ◽  
Andre Kipnis
Keyword(s):  
Infectious Disease ◽  
Amino Acids ◽  
Mycobacterium Tuberculosis ◽  
Infection Process ◽  
Tuberculosis Infection ◽  
Obligate Intracellular Bacterium ◽  
Biological Cycle ◽  
Mycobacterium Tuberculosis Infection ◽  
Peptide Bonds ◽  
Obligate Intracellular

Tuberculosis is a contagious infectious disease caused by Mycobacterium tuberculosis, an obligate intracellular bacterium that relies on infection and host to host transmission to survive. In a co-evolution process, the pathogen developed virulence mechanisms to evade the host’s immune system and endure many factors, such as cellular stress for example. One of the strategies used by pathogens to achieve success in their infection is the production of proteases, which are enzymes that cleave peptide bonds between the amino acids in a protein. Proteases are widely distributed in the nature and have different roles that are considered important to the bacteria biological cycle. M. tuberculosis have several protease coding genes in its genome, many of which with unknown function, but several with attributed role in the infection process. This review presents the literature searched between 2014 and 2018 that addressed the roles of the proteases involved in the Mycobacterium tuberculosis infection.

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