Microwave-assisted synthesis of antimicrobial agents based on pyridazine moiety

An efficient and simple microwave assisted synthesis of sulfonamide derivatives incorporating the pyridazine moiety has been developed. These sulfonamides were used for the preparation of new heterocyclic compounds via reaction with different reagents using a microwave irradiation technique. The structures of the newly synthesized compounds were confirmed on the basis of FTIR, ¹H and ¹³C-NMR, mass spectral techniques and elemental analyses. Some of the new synthesized compounds were assayed for their in vitro antibacterial activity against Gram-positive bacteria, Staphylococcus aureus and Staphylococcus epidermidis, Gram-negative bacteria, Escherichia coli and Klebsiella pneumonia and antifungal activity against Aspergillus fumigatus and Candida albicans. Most of the new compounds showed significant antibacterial and antifungal activity.     

Study on the hydrolysis mechanism of phosphodiesterase 4 using molecular dynamics simulations

We carried out NPT molecular dynamics simulations in an explicit solvent to better understand the mechanism of cyclic adenosine monophosphates (cAMP) hydrolysis by phosphodiesterase 4 (PDE4) enzyme on atomic details and to obtain information on the dynamics characteristic of the catalytic domains of PDE4. In analyzing the water hydrogen-bond network around the active site, we also showed the importance of water in drug–protein interactions. In addition, we reported the characteristics of the hydration pattern and the dynamic distance distribution around the interesting residues. The results indicated that Asp318 plays the role of a general base that can activate water molecule for nucleophilic attack on cAMP. As expected, His160 plays the role of a proton donor for cAMP.     

The MDM2 RING Domain and Central Acidic Domain Play Distinct Roles in MDM2 Protein Homodimerization and MDM2-MDMX Protein Heterodimerization

The oncoprotein murine double minute 2 (MDM2) is an E3 ligase that plays a prominent role in p53 suppression by promoting its polyubiquitination and proteasomal degradation. In its active form, MDM2 forms homodimers as well as heterodimers with the homologous protein murine double minute 4 (MDMX), both of which are thought to occur through their respective C-terminal RING (really interesting new gene) domains. In this study, using multiple MDM2 mutants, we show evidence suggesting that MDM2 homo- and heterodimerization occur through distinct mechanisms because MDM2 RING domain mutations that inhibit MDM2 interaction with MDMX do not affect MDM2 interaction with WT MDM2. Intriguingly, deletion of a portion of the MDM2 central acidic domain selectively inhibits interaction with MDM2 while leaving intact the ability of MDM2 to interact with MDMX and to ubiquitinate p53. Further analysis of an MDM2 C-terminal deletion mutant reveals that the C-terminal residues of MDM2 are required for both MDM2 and MDMX interaction. Collectively, our results suggest a model in which MDM2-MDMX heterodimerization requires the extreme C terminus and proper RING domain structure of MDM2, whereas MDM2 homodimerization requires the extreme C terminus and the central acidic domain of MDM2, suggesting that MDM2 homo- and heterodimers utilize distinct MDM2 domains. Our study is the first to report mutations capable of separating MDM2 homo- and heterodimerization.     

Substrate-enzyme interactions and catalytic mechanism in phospholipase C: a molecular modeling study using the GRID program.

Based on the high-resolution X-ray crystallographic structure of phospholipase C from Bacillus cereus, the orientation of the phosphatidylcholine substrate in the active site of the enzyme is proposed. The proposal is based on extensive calculations using the GRID program and molecular mechanics geometry relaxations. The substrate model has been constructed by successively placing phosphate, choline and diacylglycerol moieties in the positions indicated from GRID calculations. On the basis of the resulting orientation of a complete phosphatidylcholine molecule, we propose a mechanism for the hydrolysis of the substrate.     

Pollen production in some plant taxa with a supposed role in allergy in Eastern India

This paper deals with the production of pollen grains per anther per flower of 15 probably allergenic pollen producing angiospermic plant taxa growing in Eastern India. The selected plant taxa includesAilanthus excelsa, Alstonia scholaris, Argemone mexicana, Azadirachta indica, Cassia alata, C. siamea, Dalbergia sissoo, Holarrhena pubescens, Lagerstroemia speciosa, Madhuca indica, Milletia pinnata, Mimusops elengi, Morus alba, M. indica andMurraya paniculata. Among the investigated taxa,A. excelsa produces the highest number of pollen grains (1635180) followed byC. siamea (1589245) andA. mexicana (463800). The production of pollen grains is lowest inH. pubescens (2500), followed byA. scholaris (5175),A. indica (6220) andM. paniculata (11200).