Synthesis and Evaluation of Ivacaftor Derivatives with Reduced Lipophilicity.

Mutations in the unique ATP-binding cassette anion channel, the cystic fibrosis conductance regulator (CFTR), lead to the inherited fatal disease known as cystic fibrosis (CF). Ivacaftor enhances channel gating of CFTR by stabilizing its open state and has been approved as monotherapy for CF patients with CFTR gating mutations (e.g., G551D) and as part of combination therapy with lumacaftor for CFTR folding mutations (e.g., ΔF508). However, in the latter context, ivacaftor may destabilize folding-rescued ΔF508-CFTR and membrane-associated proteins and attenuate lumacaftor pharmacotherapy. Here, we tested the hypothesis that the high lipophilicity of ivacaftor may contribute to this effect. We describe the synthesis of three glutamic acid ivacaftor derivatives with reduced lipophilicity that bear different charges at neutral pH (compounds 2, 3, 4). In a cellular ion flux assay, all three restored G551D-CFTR channel activity at comparable or better levels than ivacaftor. Furthermore, unlike ivacaftor, compound 3 did not attenuate levels of folding-rescued ΔF508 at the cell surface. Molecular modeling predicts that the increased polarity of compound 3 allows engagement with polar amino acids present in the binding pocket with hydrogen bonding and ionic interactions, which are collectively higher in strength as compared to hydrophobic interactions that stabilize ivacaftor. Overall, the data suggests that reduced lipophilicity may improve the efficacy of this class of CFTR potentiators when used for folding-rescued ΔF508-CFTR.

Elevated Fibrinogen Level Reduces Therapeutic Efficiency of AD Drugs: Biophysical Insights into the Interaction of FDA-Approved Cholinesterase Inhibitors with Human Fibrinogen.

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 FDA-approved 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 IC50 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.

Molecular docking analysis of arjunolic acid from Terminalia arjuna with a coronary artery disease target APOE4.

Apo lipoprotein-E (APOE) encoded by APOE gene, is a plasma glycoprotein of 34.15 kDa and has a significant genetic association in coronary artery disease (CAD) progression. The silent epidemic of different cardiovascular diseases including CAD challenges novel therapeutic alternatives to prevent to treat chronic conditions of the disease and its associated complications. It is believed that natural phyto compounds and extracts have been a potential source of treating health conditions and have been practiced since several decades. The aim of the study is to identify phyto compounds having significant cardio protective activity targeting APOE4. Since protein-ligand interactions play a leading role in structure-based drug design, with the help of molecular docking, we selected 20 phyto chemicals present in different plants and investigated their binding affinity against targeted APOE isoforms. Among all selected phytoc ompounds, arjunolic acid, from Terminalia arjuna plant was found as promising candidate for developing therapeutic against APOE4 activated CAD. Findings from the present work could be further studied for clinical evaluations on human to adopt strategies and reduce the prevalence and mortality. Arjunolic acid derivatives can be used as a source of new medication or development of novel compounds in the treatment of CAD.

PDZscape: a comprehensive PDZ-protein database.

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 .