International Journal of Drug Discovery

160-163

Authors: JADHAV S.V., JADHAV R., GANDHAM N., MISRA R., SINGH P., UJAGARE M., ANGADI K., VYAWAHARE C.

The rising rate of antimicrobial drug resistance in Enterobacteriaceae reduces the number of reliably effective drugs that can be used to treat infections. Gram negative bacteria producing β-lactamases that are resistant to many other antibiotics and very few antimicrobial agents remain effective as treatment option. Since the initial description of Extended Spectrum β-lactamases (ESBLs) production by Klebseilla pneumonia & Escherichia coli in the 1980s, strains of Enterobacteriaceae resistant to third-generation cephalosporins are increasingly being recognized globally. ESBL-producing Enterobacteriaceae strains have been frequently implicated in outbreaks in all intensive care units especially pediatric Intensive Care Unit (PICUs) and Neonatal Intensive Care Unit (NICU). Therefore, there have been many recent calls to intensify current infection control efforts aimed at reducing the emergence and dissemination of infections caused by antibiotic-resistant bacteria. The widespread use of Cefriaxone and/or cefotaximine has been proposed as a reason for the emergence of CTX-M enzymes. The increased frequency of isolation & reporting of CTX-M ESBLs is alarming and is likely to represent only the tip of iceberg for the underdeveloped continents where molecular technology for the analysis of ESBL enzymes is scares. To further delineate the mode of successful dissemination of ESBLs CTX-M-15 and to gain insights into the mechanism underlying this phenomenon we designed this study to assesses clonality & diversity of Enterobacteriaceae strains isolated from PICUs and NICUs of our hospital. Total of 100 blood samples were received from PICU and NICU during the study period of two months. 10 ESBLs were isolated from total 55 Gram negative bacteria, of that five were possessing CTX-M-15 by PCR methods.

169-172

Authors: ARUNKUMAR V.A., KESHAV MOHAN

HIV-1 protease (HIV PR) is an essential enzyme needed in the proper assembly and maturation of infectious virions. HIV PR catalyses proteolytic cleavage of the polypeptide precursors into mature enzymes and structural proteins which is a critical step in the life cycle of HIV. The necessity of this enzyme in the virus life cycle makes it a promising target for therapy of the HIV infection. In order to discover potential inhibitors of HIV PR, structure based virtual screening was performed using crystal structure of the protein obtained from PDB (2BB9). 46 Quinoxaline analogues were docked with 2BB9 and the highly interacting compounds based on their binding energies are reported here.

128-136

Authors: VOLETI S.R.

Computational techniques such as homology modeling and molecular dynamics were used to identify novel intramolecular ioniclock interactions among key charged residues spanning the transmembrane helices and extracellular loops of human complement C3a receptor and the synthetically prepared human C3a receptor ligand SB290157. The results shed light on the active site of the human C3aR and the arginine specificity of the ligand. A strong ionic-lock region with interactions among the charged residues R161 (R4.64), E162 (ER4.65), R340 (R5.42), K96 (K3.36), D167 (D4.70), D417 (D7.35) and H418 (H7.36) is critical for the structural integrity of human C3aR. Results of docking both the stereoisomer of SB290157 with human C3aR indicate that the active site consist of the aromatic residues F107 (F3.37), Y160 (Y4.63), F345 (F5.47), W390 (W6.48), Y393 (Y6.51) and F396 (F6.54) together with the ionic-lock region and reveal the lack of stereospecific preference of human C3aR for SB290157. The active site features of human C3aR and the proposed ligand-binding region may permit the discovery of novel antagonists for C3aR as potential therapeutic agents for conditions such as asthma.

145-152

Authors: ANJANA MUNSHI, SAI BABU M., VENKATESWARA RAO A., LAKSHMAN TEJA G., SUBASH KAUL, JYOTHY A.

Statins are the most prescribed drugs, highly effective in reducing the risk of cardiovascular and cerebrovascular events, primarily by lowering low density lipoprotein (LDL) cholesterol. Although large clinical trials found a 27% average relative risk reduction of major coronary events, there is large variability in benefits from statin therapy. Researchers have found three SNPs (C3435T, G2677T/A, C1236T) of MDR1gene, which codes for P-Glycoprotein (P-gp) (a drug efflux transporter), responsible for the reduced bioavailability of statins. We aimed to design a new drug molecule based on synonymous and nonsynonymous SNPs of MDR1 gene, which is not a substrate to P-gp and acts directly on ßhydroxy methylglutaryl coenzyme A reductase (HMG-CoA), a target site for statins, using Insilico tools. Structural changes in mRNA due to synonymous and nonsynonymous SNPs were evaluated by SNPfold. The 3D structures of normal and mutant proteins of P-gp and HMG-CoA reductase were modeled by Molecular Operating Environment (MOE). A new lead molecule was designed from native structure by VegaZZ and parameters of drug were validated with HyperChem and Pharmacophore mapping was done using LigandScout. We docked the lead molecule with normal and mutant P-gp and found no interactions with P-gp showing that it is not a substrate for P-gp. However, it forms clear hydrogen bond interactions with HMG-CoA reductase. This is a novel approach in the field of bioinformatics and pharmacogenomics (pharmacogenoinformatics) for the development of new drug molecules based on the SNPs of genes involved in drug metabolism in a particular population.