Investigate the protein-ligand binding affinity and evaluate the receptor binding abilities of different classes of ligands for APOE4 through molecular docking studies. The polymorphic nature of human Apo E gene encodes one of 3 common epsilon (ε) alleles (ε2, ε3, and ε4), reported to influence the risk of cardiovascular diseases. Structural basis of APOE4 involvement in CAD suggests that the intramolecular domain interactions to be a suitable target for therapeutic intervention. Identification of APOE4 modulators, targeted towards therapeutic candidates in CAD using Molecular Docking studies. Various classes of ligands including known drugs used in the treatment of CAD, fragment-based stabilizers and their similar structures and molecules with known bioactivity against APOE4 were screened for their binding affinity and further investigated for their interactions with APOE4. Computational studies show the benzyl amide derived structures to be useful candidates in modulation of APOE4. The protein-ligand binding affinities predicted in the study indicated receptor binding abilities of APOE4 that can lead to have interesting insights on structural conformity of APOE4 and its correlated functional aspects. Understanding modulation of APOE4 can pave ways to use it as biomarker for CAD as well as for its therapeutics. Further analysis of the variation of the docked protein structure, molecular dynamic simulation can be performed to generate a dynamic structure for binding analysis.

Despite being the second most abundant protein in blood plasma, reports on the interaction of drugs with fibrinogen (FIB) are relatively scarce. The effect of FIB on the therapeutic potency of four FDAapproved Alzheimer's disease drugs, namely, tacrine (TAC), donepezil (DON), eserine (ESE), and huperzine (HUP), was investigated through a combination of different in vitro and in silico experiments. The efficiency of the drugs in inhibiting the activity of acetylcholinesterase (AChE) was significantly reduced in the presence of FIB. This effect was even found to be more substantial than that for the most abundant plasma protein, human serum albumin (HSA). For example, the relative change in IC 50 for TAC was found to be 65% in 10 μM FIB as opposed to 43% in the presence of 250 μM HSA. The relative trend of modulation in AChE activity showed consistency with the binding efficiency of the drugs and FIB. The sequestration of drugs in FIB, therefore reducing the availability of free drugs in solution, was identified to be the primary cause for the decrease in the AChE inhibition potency. This study aims to establish FIB as a vital component, while considering the therapeutic effectiveness of different newly developed AChE inhibitors.

No abstract

PDZ-containing proteins comprise one of the most widely distributed protein families playing major role in localization and membrane receptor clustering. They are hence important regulators of signal transduction in cellular pathways. Although knowledge on these proteins has increased exponentially, the existing database ‘PDZBase’ is limited by presence of only 339 proteins as it dates back to 2004 when very little data was available. Thus, lack of exclusive information on this protein family led us to develop PDZscape. ‘PDZscape’ encompasses the complete available information on 58,648 PDZ-containing proteins with their known and putative binding partners on one platform. It has a user-friendly web interface that can be easily queried with external protein identifiers. With unique integration of prominent databases including NCBI, UniProtKB, Swiss-Prot, Pubmed, PDB, STRING, IntAct, KEGG, Pfam and Protein Mutant Database, it provides detailed information on PDZ interactome apart from the customized BLAST option. Most importantly, this database encompasses the mutations and diseases associated with PDZ containing proteins manually curated by our group, thus making it a comprehensive compilation. It also features tools to query the database using sequence (PDZ-Blast) and to find if protein of interest is a PDZ-binding protein. PDZscape is freely available at http://www.actrec.gov.in:8080/pdzscape.