Plant products have always been considered for many important metabolic disorders due to its abundant medicinal properties. Alarming adverse effects of overuse of statins has been reported for patients with dyslipidemia. This study was aimed to identify compounds with potent anti-dyslipidemic property from selected plants and analyze them for their efficiency in binding with HMG-CoA reductase, a key enzyme in lipid metabolism. The docking studies indicate rutin as the best compound that can inhibit HMG-CoA reductase as it had strong binding affinity to the enzyme. The molecular dynamics simulation studies confirmed the stability of the HMG-CoA reductase-rutin complex. RMSD, RMSF, Rg, H-bond results indicated that the HMG-CoA reductase-rutin complex is highly stable. Presently, statins are not preferred for individuals with pre-existing liver disease. Our study identified rutin as a promising lead compound which could be further developed into an anti-dyslipidemic molecule. Our results will be a good starting point for future experimental and clinical studies and if the results from such studies match international standards plant derived rutin might emerge as a good alternative to statins. J. Cell. Biochem. 118: 52-57, 2017. © 2016 Wiley Periodicals, Inc.

Anand A

Department of Biotechnology

School of Bio Sciences and Technology

Vellore Campus

Suganya S

Nandagopal B

Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

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VIT University

Journal of Cellular Biochemistry

Presently, there are no effective vaccines and anti-virals for the prevention and treatment of Hepatitis C virus infections and hence there is an urgent need to develop potent HCV inhibitors. In this study, we have carried out molecular docking, molecular dynamics and 3D-QSAR on heteroaryl 3-(1,1-dioxo-2H-(1,2,4)-benzothiadizin-3-yl)-4-hydroxy-2(1H)-quinolinone series using NS5B protein. Total of 41 quinolinone derivatives is used for molecular modeling study. The binding conformation and hydrogen bond interaction of the docked complexes were analyzed to model the inhibitors. We identified the molecule XXXV that had a higher affinity with NS5B. The molecular dynamics study confirmed the stability of the compound XXXV-NS5B complex. The developed CoMFA descriptors parameters, which were calculated using a test set of 13 compounds, were statistically significant. Our results will provide useful insights and lead to design potent anti-Hepatitis C virus molecules. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Cell Biochemistry and Biophysics

Comparative Molecular Field Analysis and Molecular Docking Studies on Quinolinone Derivatives Indicate Potential Hepatitis C Virus Inhibitors

The World Health Organization reports that millions of people around the world are infected with antibiotic-resistant bacteria. Such resistance is more common in Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae strains because of the expression of the metallo-β-lactamases (MBLs) namely Imipenemase (IMP)-1, IMP-2, New Delhi metallo-β-lactamases-, Verona imipenemase (VIM)-4, VIM-5, and VIM-7. We did an in silico analysis to understand the resistance mechanism of imipenem at the structural level. Our modeling studies reveal that the VIM-4-imipenem complex has highest binding energy and forms a stable complex as indicated by a consensus score (C-score) value of 5.44. The intense interaction between the substrate and the β-lactamases leads to the increased hydrolysis of the substrate resulting in rapid hydrolysis of the antibiotic imipenem by VIM-4. Virtual screening of compounds from the ZINC database targeting VIM-4 was done, and we found compound ZINC44608383 as the high binding energy compound with the C-score value of 5.58. This compound could be exploited for inhibitor design and development. The current study helps us to understand the resistance mechanism of imipenem in MBL-expressing strains. Also, we have identified a probable inhibitor for VIM-4. We believe that our results will be useful for researchers in designing potent inhibitors for VIM-4. © 2018 Wiley Periodicals, Inc.

Mechanism of imipenem resistance in metallo‐β‐lactamases expressing pathogenic bacterial spp. and identification of potential inhibitors: An in silico approach

Prolonged antibiotic therapy for the bacterial infections has resulted in high levels of antibiotic resistance. Initially, bacteria are susceptible to the antibiotics, but can gradually develop resistance. Treating such drug-resistant bacteria remains difficult or even impossible. Hence, there is a need to develop effective drugs against bacterial pathogens. The drug discovery process is time-consuming, expensive and laborious. The traditionally available drug discovery process initiates with the identification of target as well as the most promising drug molecule, followed by the optimization of this, in-vitro, in-vivo and in pre-clinical studies to decide whether the compound has the potential to be developed as a drug molecule. Drug discovery, drug development and commercialization are complicated processes. To overcome some of these problems, there are many computational tools available for new drug discovery, which could be cost effective and less time-consuming. In-silico approaches can reduce the number of potential compounds from hundreds of thousands to the tens of thousands which could be studied for drug discovery and this results in savings of time, money and human resources. Our review is on the various computational methods employed in new drug discovery processes. © 2018, © 2018 Informa UK Limited, trading as Taylor &amp; Francis Group.

Biotechnology and Genetic Engineering Reviews

Bioinformatics approaches for new drug discovery: a review

Cholera is a serious threat to a large population in the under developed countries. Though oral rehydration therapy is the preferred choice of treatment, the use of antibiotics could reduce the microbial load in the case of severity. The use of antibiotics is also sought in the scenarios where there is problem with access to clean water. However, Vibrio cholera (V. cholerae) strains have developed resistance to antibiotics such as amoxicillin, ampicillin, chloramphenicol, doxycycline, erythromycin, and tetracycline. In this work, we have addressed the resistance issue by targeting MurB protein which is essential for the cell wall biosynthesis in V. cholerae. 20 Phytochemical compounds were chosen to screen the potential inhibitors against V. cholerae to avoid the complications faced by synthesis of small molecules. The molecular docking and dynamics study indicates that quercetin is the most potential and stable inhibitor of Murb.

MurB as a target in an alternative approach to tackle theVibrio choleraeresistance using molecular docking and simulation study

Mutations in Fetal Liver Tyrosine Kinase 3 (FLT3) genes are implicated in the constitutive activation and development of Acute Myeloid Leukaemia (AML). They are involved in signalling pathway of autonomous proliferation and block differentiation in leukaemia cells. FLT3 is considered as a promising target for the therapeutic intervention of AML. There are a few missense mutations associated with FLT3 that are found in AML patients. The D835N mutation is the most frequently observed and the aspartic acid in this position acts as a key residue for the receptor activation. The present study aims to understand the structural effect of D835N mutation in FLT3. We carried out the molecular dynamics (MD) simulation for a period of 120 ns at 300 K. Root-mean square deviation, root-mean square fluctuations, surface accessibility, radius of gyration, hydrogen bond, eigenvector projection analysis, trace of covariance matrix, and density analysis revealed the instability of mutant (D835N) protein. Our study provides new insights on the conformational changes in the mutant (D835N) structure of FLT3 protein. Our observations will be useful for researchers exploring AML and for the development of FLT3 inhibitors. © 2015 Wiley Periodicals, Inc.

Molecular Dynamics Studies on D835N Mutation in FLT3-Its Impact on FLT3 Protein Structure

Metallo Beta (β) Lactamases (MBL) are metal dependent bacterial enzymes that hydrolyze the β-lactam antibiotics. In recent years, MBL have received considerable attention because it inactivates most of the β-lactam antibiotics. Increase in dissemination of MBL encoding antibiotic resistance genes in pathogenic bacteria often results in unsuccessful treatments. Gene interaction network of MBL provides a complete understanding on the molecular basis of MBL mediated antibiotic resistance. In our present study, we have constructed the MBL network of 37 proteins with 751 functional partners from pathogenic bacterial spp. We found 12 highly interconnecting clusters. Among the 37 MBL proteins considered in the present study, 22 MBL proteins are from B3 subclass, 14 are from B1 subclass and only one is from B2 subclass. Global topological parameters are used to calculate and compare the probability of interactions in MBL proteins. Our results indicate that the proteins associated within the network have a strong influence in antibiotic resistance mechanism. Interestingly, several drug targets are identified from the constructed network. We believe that our results would be helpful for researchers exploring MBL-mediated antibiotic resistant mechanisms. © 2015 Wiley Periodicals, Inc.

Gene Network Analysis of Metallo Beta Lactamase Family Proteins Indicates the Role of Gene Partners in Antibiotic Resistance and Reveals Important Drug Targets

World Health Organization reports that methicillin-resistant Staphylococcus aureus (MRSA) is the origin of higher proportion of hospital acquired infections. In order to combat the effect of MRSA infection, an ideal drug should stimulate the allosteric exposure of active site, prompting penicillin binding proteins (PBP2a) to bind with that particular compound. Ceftaroline shows high binding affinity towards PBP2a and also confers resistance against degrading enzymes. Recently, two amino acid alterations in the allosteric site of PBP2a, asparagine (N) to lysine (K) at position 146 and glutamic acid (E) to lysine at position 150 are reported to confer resistance against ceftaroline resulting in the rise of ceftaroline-resistant MRSA strains. The present study focuses on the identification of potential ligands that can effectively bind with allosteric site of PBP2a, that leads to the access of active site and entry of a β-lactam antibiotic for effective inhibition. The results obtained from our study will be useful for designing effective compounds with potential therapeutic effects against ceftaroline resistant MRSA strains. © 2015 Wiley Periodicals, Inc.

A Molecular Docking and Dynamics Study to Screen Potent Anti-Staphylococcal Compounds Against Ceftaroline Resistant MRSA

Penicillin binding proteins are recognized as important antibacterial targets because of their crucial role in the cell wall synthesis of bacteria. Alteration in the binding site of penicillin binding proteins is one of the major problems for beta lactam antibiotics to exert its effect. In the present study the influence of CH...O interactions in the conformational stability of penicillin binding proteins were analyzed in both Gram positive and Gram negative bacteria. CH...O interactions constitute about 20 to 25% of total hydrogen bonds and act as an important driving force in ligand selectivity. From our analysis we observed a total of 13,398 CH...O interactions in Gram positive bacteria and 10,855 CH...O interactions in Gram negative bacteria. It was interesting to observe that CH...O interactions were higher in Gram positive bacteria than in Gram negative bacteria, which augurs well for the discrepancy in cell wall of the bacteria. CH...O interactions are classified into four types depending on the interaction of acceptor residues with the back bone or side chain of CH groups. From our results we observed that major contribution to penicillin binding proteins was observed from side chain atoms of donor residues and back bone atoms of acceptor residues [SM CH...O] in both Gram positive and Gram negative bacteria. Conformational preference of Gram positive bacteria indicated that amino acids lacking side chain and the cyclized amino acids preferred to be in turn regions, whereas aromatic amino acids dominated in Gram negative bacteria. Our analysis gives detailed information about the principles involved in the conformational stability of penicillin binding proteins and the results will be useful for researchers exploring penicillin binding proteins. © 2015 Elsevier Ltd.

Computers in Biology and Medicine

Investigations on the role of CH…O interactions and its impact on stability and specificity of penicillin binding proteins

Bacterial resistance to β-lactams antibiotics is a serious threat to human health. The most common cause of resistance to the β-lactams is the production of β-lactamase that inactivates β-lactams. Specifically, class A extended-spectrum β-lactamase produced by antibiotic resistant bacteria is capable of hydrolyzing extended-spectrum Cephalosporins and Monobactams. Mutations in class A β-lactamases play a crucial role in substrate and inhibitor specificity. In this present study, the E166A point mutant, R274N/R276N double mutant, and E166A/R274N/R276N triple mutant class A β-lactamases are analyzed. Molecular dynamics (MD) simulations are done to understand the consequences of mutations in class A β-lactamases. Root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessibility surface area, hydrogen bond, and essential dynamics analysis results indicate notable loss in stability for mutant class A β-lactamases. MD simulations of native and mutant structures clearly confirm that the substitution of alanine at the position of 166, Asparagine at 274 and 276 causes more flexibility in 3D space. Molecular docking results indicate the mutation in class A β-lactamases which decrease the binding affinity of Cefpirome and Ceftobiprole which are third and fifth generation Cephalosporins, respectively. MD simulation of Ceftobiprole-native and mutant type Class A β-lactamases complexes reveal that E166A/R274N/R276N mutations alter the structure and notable loss in the stability for Ceftobirole-mutant type Class A β-lactamases complexes. Ceftobiprole is currently prescribed for patients with serious bacterial infections; this phenomenon is the probable cause for the effectiveness of Ceftobiprole in controlling bacterial infections. © 2013 Taylor &amp; Francis.

Journal of Biomolecular Structure and Dynamics

Molecular dynamics and molecular docking studies on E166A point mutant, R274N/R276N double mutant, and E166A/R274N/R276N triple mutant forms of class A β-lactamases

Journal	Data powered by TypesetJournal of Cellular Biochemistry
Publisher	Data powered by TypesetWiley
ISSN	0730-2312
Open Access	0