Current Drug Discovery Technologies (v.12, #3)

Meet Our Regional Editor: by Detlev Boison (127-128).

Systems Biology Research into Cardiovascular Disease: Contributions of Lipidomics-based Approaches to Biomarker Discovery by Hector De Leon, Stephanie Boue, Justyna Szostak, Manuel C. Peitsch, Julia Hoeng (129-154).
Atherosclerosis is a progressive inflammatory thickening of the arterial wall resulting from increased cellularity and the accumulation of lipids, cellular debris, and extracellular matrix. Conventional determinations of plasma lipoproteins have resulted in a wealth of clinical data documenting the correlation between low- and high-density lipoproteins (LDL and HDL) and cardiovascular disease (CVD) risk. Current mass spectrometry methodologies allow the detection and quantification of multiple molecular lipid species with various structural and functional roles. The opportunities provided by lipidomics for lipid-based biomarker discovery are prominent in disease diagnostics, monitoring of drug efficacy, and translational model development. For example, the analysis of human plasma samples assessing the effects of statins has shown correlative effects between the LDL/HDL ratio and sphingomyelin and phosphatidylcholine. Additionally, at the vascular tissue level, lipids from different classes are enriched in human plaques of coronary arteries and in the aortas of apolipoprotein E-deficient mice exposed to cigarette smoke, highlighting a set of lipid biomarkers for translational research. Molecular lipidomics will provide insights in which other lipids may play important roles in vascular disease progression and will serve as novel markers for preventive as well as therapeutic purposes.

Elevated concentration of any or all types of lipids in the plasma including hypertriglyceridemia and hypercholesterolemia leads to atherosclerotic cardiovascular disease. Effective medication needs multiple drug therapy as recommended cholesterol and triglyceride levels are difficult to achieve by monotherapy and frequently require the use of more than one lipid-lowering medication. Gemfibrozil lowers plasma triglyceride-rich lipoproteins mainly VLDL and increases HDL. It is associated with short plasma half-life (1.5h) and GIT distress on long term use. In a study it was found that ethanolamine decreases serum cholesterol, especially VLDL cholesterol and LDL cholesterol in rats fed an HF/HC diet. In the present work, we thought of exploring the effect of co-drug of gemfibrozil with ethanolamine (GE-I) as a potential combination therapy for the management of mixed hyperlipidemia. Synthesis of GE-I was effected by CDI coupling. Structure was confirmed spectrally. Interestingly kinetic studies revealed that GE-I resisted chemical and enzymatic hydrolysis. In tritoninduced hyperlipidemia, significant lowering of serum lipid levels was observed. The hallmark of GEI was its profound effect on HDL level which was raised above the normal level by 15%. Docking study also supported modulatory effect of GE-I (docking score -7.012) on PPAR-α which was comparable to docking score of gemfibrozil (-9.432). These preliminary observations prompt us to consider GE-I as a novel, serendipitous, hybrid anti-hyperlipidemic new chemical entity which needs be studied extensively to prove it as an HDL enhancing anti-hyperlipidemic agent.

A New Scoring Function for Molecular Docking Based on AutoDock and AutoDock Vina by Vsevolod Yu. Tanchuk, Volodymyr O. Tanin, Andriy I. Vovk, Gennady Poda (170-178).
Molecular docking of small molecules in the protein binding sites is the most widely used computational technique in modern structure-based drug discovery. Although accurate prediction of binding modes of small molecules can be achieved in most cases, estimation of their binding affinities remains mediocre at best. As an attempt to improve the correlation between the inhibitory constants, pKi, and scoring, we created a new, hybrid scoring function. The new function is a linear combination of the terms of the scoring functions of AutoDock and AutoDock Vina. It was trained on 2,412 protein-ligand complexes from the PDBbind database (www.pdbbind.org.cn, version 2012) and validated on a set of 313 complexes released in the 2013 version as a test set. The new function was included in a modified version of AutoDock. The hybrid scoring function showed a statistically significant improvement in both training and test sets in terms of correlation with and root mean square and mean absolute errors in prediction of pKi values. It was also tested on the CSAR 2014 Benchmark Exercise dataset (team T) and produced reasonably good results.

Ternary Inclusion Complexes of Rifaximin with β-Cyclodextrin and Sodium Deoxycholate for Solubility Enhancement by Parminderjit Kaur, Ankit Rampal, Preet M. Singh Bedi, Neena Bedi (179-189).
Rifaximin is a rifamycin derivative, having extremely poor aqueous solubility. The objective of present study was to improve dissolution and solubility of drug using β-cyclodextrin inclusion complexes and also to evaluate the effect of presence of sodium deoxycholate on solubilization efficiency of β-cyclodextrin. The stochiometry of inclusion complexes of binary (drug-cyclodextrin) and ternary system (drug-cyclodextrin-sodium deoxycholate) were determined by phase solubility studies at 25°C. The stability constants (K1:2) calculated from phase solubility analysis were 126M-1 and 267M-1 for binary and ternary systems respectively. The inclusion complexes were prepared by solvent evaporation method with the inclusion efficiency of 43% and 56.9% for binary and ternary systems followed by their characterization using fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry and in-vitro antibacterial activity. The solubility of drug was improved by 4.3 and 11.9 folds in binary and ternary inclusion complexes, respectively. Therefore, it can be concluded that the ternary inclusion complexation having better solubilization efficiency as compared to binary complexation.