Studies on intra-protein interactions provide valuable information on protein conformation. The aim of our study is to explore the functional importance of residues participating in N-H⋯π hydrogen bonds in maintaining the conformational stability of β-lactamases. Our results show that most of the residues participating in N-H⋯π hydrogen bond formation are functionally important and play a significant role in stabilizing the structure with more than one stabilizing region. Our findings reveal the importance of N-H⋯π hydrogen bonds in the stability of β-lactamases. These findings may be helpful for medicinal and computational protein chemists working in the area of enzyme mediated antibiotic resistance. © 2013 Elsevier Ltd.

Anand A

Department of Biotechnology

School of Bio Sciences and Technology

Vellore Campus

Sudha Ramaiah

Department of Bio-Sciences

Lavanya P

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

Computers in Biology and Medicine

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.

Journal of Cellular Biochemistry

Natural Inhibitors of HMG-CoA Reductase-An Insilico Approach Through Molecular Docking and Simulation Studies

The computational studies namely molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are executed on series of 52 novel aryl chalcones derivatives using Plasmodium falciparum cysteine proteases (falcipain - 2) as vital target. In the present study, the correlation between different molecular field effects namely steric and electrostatic interactions and chemical structures to the inhibitory activities of novel aryl chalcone derivatives is inferred to perceive the major structural prerequisites for the rational design and development of potent and novel lead anti-malarial compound. The apparent binding conformations of all the compounds at the active site of falcipain - 2 and the hydrogen-bond interactions which could be used to modify the inhibitory activities are identified by using Surflex-dock study. Statistically significant CoMFA model has been developed with the cross-validated correlation coefficient (q2) of 0.912 and the non-cross-validated correlation coefficient (r2) of 0.901. Standard error of estimation (SEE) of 0.210, with the optimum number of components is ten. The predictability of the derived model is examined with a test set consists of sixteen compounds and the predicted r2 value is found to be 0.924. The docking and QSAR study results confer crucial suggestions for the optimization of novel 1,3-diphenyl-2-propen-1-one derivatives and synthesis of effective anti- malarial compounds. © 2016 Elsevier Ltd.

Journal of Theoretical Biology

Comparative molecular field analysis and molecular docking studies on novel aryl chalcone derivatives against an important drug target cysteine protease in Plasmodium falciparum

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium that frequently causes nosocomial infections. New generation cephalosporins and β-lactams along with inhibitors are used for the treatment of opportunistic bacterial infections. The indiscriminate use of antibiotics has led to the emergence of bacterial resistance. Carbapenem class of antibiotics like imipenem and meropenem are currently the final line of antibiotics for the treatment of infections caused by multidrug-resistant P. aeruginosa. Recent reports indicate that P. aeruginosa has acquired resistance to imipenem through a class D oxacillinase-OXA-10 extended spectrum β-lactamase (ESBL). OXA-10 ESBL is encoded by the gene blaOXA-10. There is an urgent need to develop OXA-10 ESBL non-hydrolysing inhibitors. We have attempted to locate OXA-10 ESBL inhibitors by performing molecular docking and molecular dynamics studies on OXA-10 ESBL with imipenem analogues from ZINC database as well as employing imipenem to understand the mechanism of resistance at the structural level. Our in-silico analysis of imipenem analogues reveals that ZINC44672480 has ideal characteristics for a potent OXA-10 ESBL non-hydrolysing inhibitor. We believe that the results from our study will provide valuable insights into the mechanism of drug resistance and aid in designing potent inhibitors against OXA-10 ESBL producing P. aeruginosa.

Cell Biochemistry and Biophysics

Molecular Docking and Molecular Dynamics Studies to Identify Potential OXA-10 Extended Spectrum β-Lactamase Non-hydrolysing Inhibitors for Pseudomonas aeruginosa

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.

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

β-Lactamase production is the common mechanism of resistance of β-lactam antibiotics. Knowledge of inter-residue interactions in protein structures increases our understanding of protein structure and stability. We have systematically analysed the contribution of C-H···π interactions to the stability of β-lactamases. Most of the interactions are long range and most of the interacting residues are evolutionarily conserved. The occurrence of C-H···π interactions in active sites and metal binding sites is very low in β-lactamases. Hence, C-H···π interactions are important determinants of stability in β-lactamases and they may not play a significant role in specificity. The results from this study provide valuable insights for understanding the stability patterns of β-lactamases and their relation to various other environmental preferences. © 2013 SBIC.

JBIC Journal of Biological Inorganic Chemistry

Non-canonical H-bonds in β-lactamases: importance of C–H···π interactions

β-lactam group of antibiotics is the most widely used therapeutic molecules for treating bacterial infections. The main mode of bacterial resistance to β-lactams is by β-lactamases. In the present study, we report our results on the role of cation-π interactions in β-lactamases and their environmental preferences. The number of interactions formed by arginine is higher than lysine in the cationic group, while tyrosine is comparatively higher than phenylalanine and tryptophan in the π group. Our results indicate that cation-π interactions might play an important role in the global conformational stability of β-lactamases.

Cation–π Interactions in β-Lactamases: The Role in Structural Stability

We have investigated the roles played by C-H⋯π interactions in RNA binding proteins. There was an average of 55 C-H⋯π interactions per protein and also there was an average of one significant C-H⋯π interaction for every nine residues in the 59 RNA binding proteins studied. Main-chain to side-chain C-H⋯π interactions is the predominant type of interactions in RNA binding proteins. The donor atom contribution to C-H⋯π interactions was mainly from Phe, Tyr, Trp, Pro, Gly, Lys, His and Ala residues. The acceptor atom contribution to main-chain to side-chain C-H⋯π and side-chain to side-chain C-H⋯π interactions was mainly from Phe and Tyr residues. On the contrary, the acceptor atoms of Trp residues contributed to all the four types of C-H⋯π interactions. Also, Trp contributed both donor and acceptor atoms in main-chain to side-chain, main-chain to side-chain five-member aromatic ring and side-chain to side-chain C-H⋯π interactions. The secondary structure preference analysis of C-H⋯π interacting residues showed that, Arg, Gln, Glu, His, Ile, Leu, Lys, Met, Phe and Tyr preferred to be in helix, while Ala, Asp, Cys, Gly, Trp and Val preferred to be in strand conformation. Long-range C-H⋯π interactions are the predominant type of interactions in RNA binding proteins. More than 50% of C-H⋯π interacting residues had a higher conservation score. Significant percentage of C-H⋯π interacting residues had one or more stabilization centers. Seven percent of the theoretically predicted stabilizing residues were also involved in C-H⋯π interactions and hence these residues may also contribute additional stability to RNA binding proteins. © 2007 Elsevier B.V. All rights reserved.

International Journal of Biological Macromolecules

Investigations on C–H⋯π interactions in RNA binding proteins

The roles played by the non-covalent interactions have been investigated for a set of six TNF proteins and nine Interleukins. The stabilizing residues have been identified by a consensus approach using the concepts of available surface area, medium and long-range interactions and conservation of amino acid residues. The cation-π interactions have been computed based on a geometric approach such as distance and energy criteria. We identified an average of 1 energetically significant cation-π interactions in every 94 residues in TNF proteins and 1 in every 62 residues in Interleukins. In TNF proteins, the cationic groups Lys preferred to be in helix while Arg preferred to be in strand regions while in Interleukins the Arg residues preferred to be in helix and Lys preferred to be in strand regions. From the available surface area calculations, we found that, almost all the cation and π residues in TNF proteins and Interleukins were either in buried or partially buried regions and none of them in the exposed regions. Medium and long-range interactions were predominant in both TNF proteins and Interleukins. It was observed that the percentage of stabilizing centers were more in TNF proteins as compared to the Interleukins, while the percentage of conserved residues were more in Interleukins than in TNF proteins. In the stabilizing residues Lys was observed to be a stabilizing residue in both TNF proteins and Interleukins. Among the aromatic group, Phe was seen to be a stabilizing residue in both TNF and Interleukins. We suggest that this study on the computation of cation-π interactions in TNF proteins and Interleukins would be very helpful in further understanding the structure, stability and functional similarity of these proteins. © 2006 Elsevier Ltd. All rights reserved.

Journal	Data powered by TypesetComputers in Biology and Medicine
Publisher	Data powered by TypesetElsevier BV
ISSN	0010-4825
Open Access	0