Docking studies of Nickel-Peptide deformylase (PDF) inhibitors: Exploring the new binding pockets

2006 ◽  
Vol 122 (1) ◽  
pp. 43-49 ◽  
Author(s):  
Qiang Wang ◽  
Datong Zhang ◽  
Jianwu Wang ◽  
Zhengting Cai ◽  
Weiren Xu
Keyword(s):  
Docking Studies ◽  
Peptide Deformylase ◽  
Binding Pockets

scholarly journals Multidrug Resistance in Neisseria gonorrhoeae: Identification of Functionally Important Residues in the MtrD Efflux Protein

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Mohsen Chitsaz ◽  
Lauren Booth ◽  
Mitchell T. Blyth ◽  
Megan L. O’Mara ◽  
Melissa H. Brown
Keyword(s):  
Molecular Dynamics ◽  
Multidrug Resistance ◽  
Neisseria Gonorrhoeae ◽  
Molecular Dynamics Simulations ◽  
Docking Studies ◽  
Drug Binding ◽  
Multidrug Efflux ◽  
Content Type ◽  
Binding Pockets ◽  
Dynamics Simulations

ABSTRACT A key mechanism that Neisseria gonorrhoeae uses to achieve multidrug resistance is the expulsion of structurally different antimicrobials by the MtrD multidrug efflux protein. MtrD resembles the homologous Escherichia coli AcrB efflux protein with several common structural features, including an open cleft containing putative access and deep binding pockets proposed to interact with substrates. A highly discriminating N. gonorrhoeae strain, with the MtrD and NorM multidrug efflux pumps inactivated, was constructed and used to confirm and extend the substrate profile of MtrD to include 14 new compounds. The structural basis of substrate interactions with MtrD was interrogated by a combination of long-timescale molecular dynamics simulations and docking studies together with site-directed mutagenesis of selected residues. Of the MtrD mutants generated, only one (S611A) retained a wild-type (WT) resistance profile, while others (F136A, F176A, I605A, F610A, F612C, and F623C) showed reduced resistance to different antimicrobial compounds. Docking studies of eight MtrD substrates confirmed that many of the mutated residues play important nonspecific roles in binding to these substrates. Long-timescale molecular dynamics simulations of MtrD with its substrate progesterone showed the spontaneous binding of the substrate to the access pocket of the binding cleft and its subsequent penetration into the deep binding pocket, allowing the permeation pathway for a substrate through this important resistance mechanism to be identified. These findings provide a detailed picture of the interaction of MtrD with substrates that can be used as a basis for rational antibiotic and inhibitor design. IMPORTANCE With over 78 million new infections globally each year, gonorrhea remains a frustratingly common infection. Continuous development and spread of antimicrobial-resistant strains of Neisseria gonorrhoeae, the causative agent of gonorrhea, have posed a serious threat to public health. One of the mechanisms in N. gonorrhoeae involved in resistance to multiple drugs is performed by the MtrD multidrug resistance efflux pump. This study demonstrated that the MtrD pump has a broader substrate specificity than previously proposed and identified a cluster of residues important for drug binding and translocation. Additionally, a permeation pathway for the MtrD substrate progesterone actively moving through the protein was determined, revealing key interactions within the putative MtrD drug binding pockets. Identification of functionally important residues and substrate-protein interactions of the MtrD protein is crucial to develop future strategies for the treatment of multidrug-resistant gonorrhea.

Structural Comparison of Ligand-Binding Domains in Estrogen-Related Receptors

2005 ◽  
Vol 277-279 ◽  
pp. 107-112
Author(s):  
Hye Yeon Kim ◽  
Ae Nim Pae ◽  
Yeon Joo Lee ◽  
Joon Kyu Park ◽  
Dae Sung Kim ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Model Building ◽  
Homology Model ◽  
Docking Studies ◽  
Antagonistic Effect ◽  
Orphan Nuclear Receptors ◽  
Binding Domains ◽  
Binding Pockets ◽  
Significant Amino Acid Sequence ◽  
Significant Amino Acid

Estrogen-related receptors (ERRs), orphan nuclear receptors, share a significant amino acid sequence homology with estrogen receptors (ERs), yet their ligands do not respond in the same manner. In fact, some of the ligands that are known as agonists of ERs show antagonistic effect in ERRs. Accordingly, the current study investigated the structures of the ligand-binding domains using homology model building and docking studies. The results showed clear differences between the ligand-binding pockets of ERRs and ERs, thereby providing structural insights into the activities related to the ligands.

Molecular Docking Studies of Sesquiterpenoids against Helicobacter pylori Peptide Deformylase

2016 ◽  
Vol 10 (3) ◽  
pp. 1-7 ◽  
Author(s):  
Muhammad Dawood ◽  
Nighat Fatima ◽  
Amara Mumtaz ◽  
Sidra Rehman ◽  
Irum Shazadi ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Molecular Docking ◽  
Docking Studies ◽  
Peptide Deformylase ◽  
Molecular Docking Studies

scholarly journals Identification of Novel Fusion Inhibitors of Influenza A Virus by Chemical Genetics

2015 ◽  
Vol 90 (5) ◽  
pp. 2690-2701 ◽  
Author(s):  
Kin Kui Lai ◽  
Nam Nam Cheung ◽  
Fang Yang ◽  
Jun Dai ◽  
Li Liu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Influenza A Virus ◽  
Influenza A ◽  
Chemical Genetics ◽  
Docking Studies ◽  
Influenza A Viruses ◽  
Fusion Inhibitors ◽  
Close Proximity ◽  
Binding Pockets ◽  
Group 1

ABSTRACTA previous screening of more than 50,000 compounds led to the identification of a pool of bioactive small molecules with inhibitory effect on the influenza A virus. One of these compounds, now widely known as nucleozin, is a small molecule that targets the influenza A virus nucleoprotein. Here we identify and characterize two structurally different novel fusion inhibitors of the influenza A virus group 1 hemagglutinin (HA), FA-583 and FA-617, with low nanomolar activities. Escape mutants that are highly resistant to each of these compounds were generated, and both were found to carry mutations localized in close proximity to the B-loop of the hemagglutinin 2 protein, which plays a crucial role in the virion-host cell fusion process. Recombinant virus, generated through reverse genetics, confirmed the resistance phenotype. In addition, the proposed binding pockets predicted by molecular docking studies are in accordance with the resistance-bearing mutation sites. We show through mechanistic studies that FA-583 and FA-617 act as fusion inhibitors by prohibiting the low-pH-induced conformational change of hemagglutinin. Our study has offered concrete biological and mechanistic explorations for the strategic development of novel fusion inhibitors of influenza A viruses.IMPORTANCEHere we report two structurally distinctive novel fusion inhibitors of influenza A virus that act by interfering with the structural change of HA at acidic pH, a process necessary for successful entry of the virus. Mutational and molecular docking studies have identified their binding pockets situated in close proximity to the B-loop region of hemagglutinin 2. The reduced sensitivity of FA-583- or FA-617-associated mutants to another compound suggests a close proximity and even partial overlap of their binding sites on hemagglutinin. Amino acid sequence alignments and crystal structure analyses of group 1 and group 2 hemagglutinins have shed light on the possible binding mode of these two compounds. This report offers new lead compounds for the design of fusion inhibitors for influenza A viruses and further shows that analysis by forward chemical genetics is a highly effective approach for the identification of novel compounds that can perturb the infectivity of viruses and to probe new druggable targets or druggable domains in various viruses.

scholarly journals Identification of Novel Glycogen Synthase Kinase-3? Inhibitor through Combined Shape-Based Screening and Molecular Docking Approach

2017 ◽  
Vol 9 (3) ◽  
Author(s):  
Navneet Chauhan ◽  
Anuradha Gajjar ◽  
Rueban Jacob Anicattu Issac ◽  
Sravan Kumar Pucha ◽  
Premkumar Arumugam
Keyword(s):  
Drug Target ◽  
Glycogen Synthase ◽  
Docking Studies ◽  
Glycogen Synthase Kinase ◽  
Kinase Assay ◽  
Glycogen Synthase Kinase 3 ◽  
Therapeutic Drug ◽  
Docking Approach ◽  
Binding Pockets ◽  
Virtual Screening Approach

Glycogen synthase kinase-3? (GSK-3?) is an important class of therapeutic drug target currently receiving wide attention. In our computational approach, shape-based similarity search was used to screen the SPECS database, based on the shape of Tideglusib molecule; a known GSK-3? inhibitor. The resulting virtual hits were applied for docking studies on the known binding pockets of GSK-3?. A novel compound [7,10-dioxo-4,5-dihydro-7H,10H-pyrano[3,2,1-ij]quinolin-8-yl acetate] proposed from docking results in the substrate site of GSK-3? was found to have inhibitory activity (IC50) above 100?M concentration in ADP-GloTM Kinase assay. This communication aims to put forward in identifying newer hit on GSK-3? target via virtual screening approach.

The Discovery of Antibacterial Natural Compound Based on Peptide Deformylase

2018 ◽  
Vol 21 (4) ◽  
pp. 292-297 ◽  
Author(s):  
Li Liang ◽  
Qianqian Zhou ◽  
Zhixiang Hao ◽  
Fanfan Wang ◽  
Yasheng Zhu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activities ◽  
Docking Studies ◽  
Peptide Deformylase ◽  
Antibacterial Drug ◽  
Binding Interaction ◽  
Docking Score ◽  
Human Infections ◽  
Antibacterial Drug Target ◽  
Mic Value

Background: In recent years, Staphylococcus aureus have developed resistance to medicines used for the treatment of human infections. Therefore, the search for antibacterial agents of high potency against Staphylococcus aureus is of great concern. Peptide deformylase (PDF), a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins, has been considered to be an important antibacterial drug target. Objective: To discover novel antibacterial drugs based on Staphylococcus aureus peptide deformylase. Method: PDF-based virtual screening of compounds from Traditional Chinese Medicine Database@Taiwan was performed by Sybyl X2.1 Surflex dock software. Compounds which possess high docking score were used for the following antibacterial experiments to evaluate their antibacterial activities. Kanamycin was also used in the antibacterial experiment as a control substance in the assay. Furthermore, molecular docking studies was applied to elucidate binding interaction between some compounds and PDF. In silico pharmacokinetic and toxicity prediction was explored to explain the reasons why these compounds might stand good chance of providing some pharmaceutical benefits. Results: Gentiopicroside, protosappanin B, dihydromyricetin and cryptochlorogenic acid with high docking score were used for our subsequent antibacterial assays. The Minimum Inhibitory Concentration (MIC) of kanamycin and gentiopicroside were 0.008 mg·mL-1 and 0.431 mg·mL-1, respectively, other three compounds, protosappanin B, dihydromyricetin and cryptochlorogenic acid have close MIC value of 0.50 mg·mL-1. Conclusion: Dihydromyricetin, with the MIC value of 0.50 mg·mL-1 and relatively high drug score of 0.82, may serve as a novel antibacterial lead compound.

scholarly journals 1,3,4-Oxadiazole Derivatives: Synthesis, Characterization, Antimicrobial Potential, and Computational Studies

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Suman Bala ◽  
Sunil Kamboj ◽  
Anu Kajal ◽  
Vipin Saini ◽  
Deo Nanadan Prasad
Keyword(s):  
Antibacterial Activity ◽  
Docking Studies ◽  
Peptide Deformylase ◽  
Biological Assessment ◽  
Computer Assisted ◽  
Amino Acid Residues ◽  
Qsar Analysis ◽  
H Nmr ◽  
Oxadiazole Derivatives ◽  
Microbial Strains

We report the synthesis and biological assessment of 1,3,4-oxadiazole substituted 24 derivatives as novel, potential antibacterial agents. The structures of the newly synthesized derivatives were established by the combined practice of UV, IR,1H NMR,13C NMR, and mass spectrometry. Further these synthesized derivatives were subjected to antibacterial activity against all the selected microbial strains in comparison with amoxicillin and cefixime. The antibacterial activity of synthesized derivatives was correlated with their physicochemical and structural properties by QSAR analysis using computer assisted multiple regression analysis and four sound predictive models were generated with goodR2,Radj2, and Fischer statistic. The derivatives with potent antibacterial activity were subjected to molecular docking studies to investigate the interactions between the active derivatives and amino acid residues existing in the active site of peptide deformylase to assess their antibacterial potential as peptide deformylase inhibitor.

3D-QSAR and molecular docking studies of hydroxamic acids as peptide deformylase inhibitors

2011 ◽  
Vol 21 (8) ◽  
pp. 1597-1610 ◽  
Author(s):  
Jian Gao ◽  
Yuanhua Cheng ◽  
Wei Cui ◽  
Quan Chen ◽  
Fushi Zhang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
3D Qsar ◽  
Hydroxamic Acids ◽  
Docking Studies ◽  
Peptide Deformylase ◽  
Molecular Docking Studies

scholarly journals Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

2021 ◽  
Vol 22 (6) ◽  
pp. 2977
Author(s):  
Ahmed Abdelaal Ahmed Mahmoud M. Alkhatip ◽  
Michail Georgakis ◽  
Lucio R. Montero Valenzuela ◽  
Mohamed Hamza ◽  
Ehab Farag ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Study ◽  
Docking Studies ◽  
Binding Energies ◽  
Spike Protein ◽  
Molecular Docking Study ◽  
In Silico Docking ◽  
Main Protease ◽  
Binding Pockets

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at −8.3 kcal/mol, followed by Zn and Ca at −8.0 kcal/mol, and Fe and Mg at −7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn–Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.

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