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.

Sudha Ramaiah

Department of Bio-Sciences

School of Bio Sciences and Technology

Vellore Campus

Anand A

Department of Biotechnology

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

Cell Biochemistry and Biophysics

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.

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

Proteins bind with one or more metal ions in their native state to facilitate the biological function of the protein. The study of critical interactions between the biological molecules and metals is an important field of study. In this work, we focus on the functional specificity of residues coordinating with the metals commonly found in β-lactamases, Zn, Mg, Na, Cu, Mn, Ni, Fe, K, and Cd through non-classical interactions. All the residues located in the metal-binding site of β-lactamases are involved in non-classical interactions. The data obtained from this study will be useful to understand the functional role of metal-coordinating residues in the specificity of β-lactamases, thus offering promising strategy to design effective β-lactamase inhibitors. © 2014 Taylor &amp; Francis.

Journal of Coordination Chemistry

Binding site residues in β-lactamases: role in non-classical interactions and metal binding

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.

Computers in Biology and Medicine

Computational analysis of N–H⋯π interactions and its impact on the structural stability of β-lactamases

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Bioinformation

Arginine and Lysine interactions with p residues in metalloproteins

Cell adhesion molecules are important for their various roles in many cellular events and responses. In the present study, we have analyzed the roles played by cation-π interactions in the structural stability of adhesion molecules. These interactions are mainly formed by long-range contacts. The occurrence of arginine is higher than lysine to form cation-π interactions. The secondary structure preferences of interacting residues are independent of amino acid class. Cation-π interactions might stabilize the interface between the terminus and core in this class of proteins. The results obtained in the present study will be useful in understanding the contribution of cation-π interactions to the overall stability of adhesion proteins. © 2010 Springer-Verlag.

Protoplasma

Structural stability studies in adhesion molecules—role of cation–π interactions

We have investigated the role of cation-pi interactions on translation elongation factors. In our investigation, an average of four significant cation-pi interactions were found, that is, an average of one cation-pi interaction per 44 residues in the ten elongation factors were observed. The analysis on the influence of short (&lt; + or - 4), medium (&gt; + or - 4 to &lt; + or - 20) and long (&gt;20) range contacts showed that cation-pi interactions are mainly formed by medium and long-range contacts. Arg-Tyr pair was found largest in number but energetic contribution of Arg-Trp pair was found most. Preferred secondary structural conformation analysis of the residues involved in cation-pi interaction indicates that the cationic Arg prefers to be in helix and Lys having equal probability for helix and strand, whereas the aromatic Phe and Trp were found mostly in helix while Tyr in strand regions. The cation-pi interaction residues involved in these proteins were found highly conserved with 48.86% residues having conservation score of &gt; or = 6. Analysis of secondary structure preference of the energetically significant cation-pi residues in different solvent accessible range indicates that most of the pi residues are found buried or partially buried whereas cationic residues were found mostly at the protein surface. The results presented in this study will be useful for structural stability studies in translation elongation factors.

Influence of cation–π interactions to the structural stability of prokaryotic and eukaryotic translation elongation factors

Journal of Microbial & Biochemical Technology

Role of Cation-π Interactions in the Structural Stability of Bacterial Exotoxins

We have analyzed and compared the influence of cation-π interactions in glycoproteins (GPs), lipid-binding proteins (LBPs) and RNA-binding proteins (RBPs) in this study. We observed that all the proteins included in the study had profound cation-π interactions. There is an average of one energetically significant cation-π interaction for every 71 residues in GPs, for every 58 residues in LBPs and for every 64 residues in RBPs. Long-range contacts are predominant in all the three types of proteins studied. The pair-wise cation-π interaction energy between the positively charged and aromatic residues shows that Arg-Trp pair energy was the strongest among all six possible pairs in all the three types of proteins studied. There were considerable differences in the preference of cation-π interacting residues to different secondary structure elements and ASA and these might contribute to differences in biochemical functions of GPs, LBPs and RBPs. It was interesting to note that all the five residues involved in cation-π interactions were found to have stabilization centers in GPs, LBPs and RBPs. Majority of the cation-π interacting residues investigated in the present study had a conservation score of ≥6, the cutoff value used to identify the stabilizing residues. A small percentage of cation-π interacting residues were also present as stabilizing residues. The cation-π interaction-forming residues play an important role in the structural stability of in GPs, LBPs and RBPs. The results obtained in this study will be helpful in further understanding the stability, specificity and differences in the biochemical functions of GPs, LBPs and RBPs. © 2007 Elsevier Ltd. All rights reserved.

Journal	Data powered by TypesetCell Biochemistry and Biophysics
Publisher	Data powered by TypesetSpringer Science and Business Media LLC
ISSN	1085-9195
Open Access	0