Combinatorial Chemistry & High Throughput Screening - Volume 15, Issue 1, 2012

The Aims and Scope of Combinatorial Chemistry & High Throughput Screening have never been more relevant than now. ‘Combinatorial Chemistry’ and ‘High Throughput Screening’ have become established disciplines over the last few years. The two disciplines are interdependent, and one cannot thrive and flourish without the other. There are about 15 million compounds available for use in HTS endeavors, and it is this availability, and the maturation in technology and pricing (liquid handling robotics, HTS-amenable assay technology platforms, reagents, signal detection platforms, etc) that have made HTS a reality in the academic sector. In addition to the HTS laboratories that exist in the pharmaceutical and biotech industries, there are about 85 open access HTS centers in the public sector worldwide. The US NIH Roadmap program and the newly organized EU-Open Screen have greatly influenced the global drug discovery landscape. Likewise, India and China have stepped up their drug discovery research infrastructure. The recently formed International Chemical Biology Society, an independent, nonprofit organization, is dedicating itself to promote research and educational opportunities at the interface of chemistry and biology, by providing an important international forum that brings together cross-disciplinary scientists from academia, nonprofit organizations, government, and industry to communicate new research and help translate the power of chemical biology to advance human health. Yours truly is the Founding President. Although there are about 7000 diseases that afflict mankind, treatments are available only for ∼200 diseases. With the genetic basis for most of these diseases known, there is a large repertoire of undrugged thlsquoerapeutic targets to explore. While the pharmaceutical industry constrained by its reliance on relative risk (low): reward (high) bias in undertaking new therapeutic areas, academia is uniquely positioned to research and develop, with the availability of vendor supplied chemistries and inhouse HTS core facilities, targeted therapies for many of these rare and neglected diseases. The newly funded NIH's National Center for Advancing Translational Sciences (NCATS) has taken a giant step towards advancing translational medicine and in finding medications for rare diseases by taking a faster route through drug repurposing. As most of the ‘low hanging fruits’ have been plucked, HTS and drug repurposing are the main avenues for finding new leads. Several myths about HTS have been dispelled unequivocally. The origins of almost 20 of the 60 drugs that have been FDA approved over the span of last 20 years could directly be traced to in-house HTS campaigns, thus dispelling the question often asked: what has HTS contributed. During the same period, 143 of the 1541 FDA approvals were discovered through public sector research. But most importantly, 9 of the 10 drugs approved for new Indications are from public sector research, thus affirming academia's leading role in finding cures for rare and neglected diseases. About 80 percent of the marketed drugs are natural products, natural product analogs or synthetic drugs based on natural product scaffolds. However, almost 80 percent of the core ring scaffolds present in the known natural products are surprisingly absent among commercially available molecules, and by extension in the screening libraries. The chemical library vendors should take note of this and make a conscientious effort to expand the chemical scaffold diversity in their combinatorial chemistry-derived compound collections. In academia, the screening libraries are almost entirely vendor-supplied. Efforts should be made to include institutional legacy compounds as part of the HTS chemical archives. If these suggestions are earnestly acted upon, the productivity of HTS campaigns in generating hits for subsequent medicinal chemistry optimization would certainly be vastly improved. It is also conceivable that we would have many more drugs targeting a wide variety of targets. ‘Combinatorial Chemistry’ and ‘High Throughput Screening’ can then unequivocally claim that these two interdependent disciplines are mandatory in expediting the modern drug discovery process. CCHTS continues to be the journal of choice for the practitioners of combinatorial chemistry, high throughput screening and allied sciences. For the year 2011, we have published 82 articles, with almost 80% of articles coming from academia. Thirty one articles are from researchers in the United States of America, and 24 each from Asia and Europe. Six of the ten issues published are the theme-based ‘Hot Topic’ issues, which are becoming quite popular. We have also introduced News and Patents section to capture discoveries pertinent to our readership. To fully support the review process of pharmacognosy-related manuscripts, we now have a new section in CCHTS on pharmacognosy, managed by Professor David Horgen, Hawaii Pacific University. During the year, Dr. Thomas Webb stepped down as the Section Editor for Combinatorial Chemistry due to increasing demands on his time. I am grateful for the exceptional services he provided during his tenure. The mantle is now taken up by Dr. Nathan Collins, Executive Director of Drug Discovery, Bioscience Division at SRI International. We are continuing to strive for publishing exceptional quality articles and that could only be done with outstanding manuscript submissions, and expert peer review process. My gratitude goes to the authors, reviewers, section editors and publishing staff for their time, advice, expertise, tireless effort, and most importantly, for upholding the high standards for content and quality of the manuscripts accepted for publication in the journal. Together, we have taken many positive steps in improving the journal. The Impact Factor for the journal has inched upwards to 2.573, according to 2010 SCI Journal Citation Reports. By the time this issue lands in the hands of the readership, I would be in my new position at SRI International (Harrisonburg, Virginia, USA) as Senior Director-Exploratory Research, and Deputy Director-Center for Advanced Drug Research. I thank the University of Kansas for giving me the freedom and resources in leading the journal for the past two years.

This paper reviews the functional polymer membrane and membrane based cell drug evaluation models for drug discovery. Based on the characteristics of biological membranes in vivo, chemical modification methods of synthetic membrane, including blending and surface modification are explored to mitigate the membrane fouling and improve biocompatibility. Different membrane-based cell models used in drug investigation and related trouble shooting are analyzed in detail. Specific attention is given to the current studies on ADME/Tox of drugs using membrane-based in vitro models of cells including Caco-2, hepatocytes or renal cells, which can be used to evaluate the feasibility of polymer membrane in drug investigation. The progress toward solving present bottlenecks of the facilitated cell models are supposed to provide great benefits to drug discovery in pharmaceutical industry.

State-of-the-art technologies and methodologies in NMR spectroscopy make it possible to obtain very informative and high-quality spectra in much less experimental time than classical methods by making better choices of NMR pulse sequences and acquisition parameters. This review presents some recent NMR methods allowing rapid identification, assignment and structural characterization of the components in mixtures. The relative merits of the different NMR pulse sequences are briefly discussed and recommendations are made for the preferred choice of sequences to obtain rapidly artifact-free data. This review covers diffusion experiments (DOSY), HSQC and HMBC experiments, ultra-resolved 2D spectra exploiting the property of aliasing and NOESY/ROESY experiments. It will be in particular shown that selective 1D NOESY/ROESY sequences can be more informative and reach higher resolution in less experimental time than the corresponding 2D sequences.

We have previously examined the binding patterns of various substrates to human cytochrome P450 2D6 (CYP2D6) using a series of molecular modeling methods. In this study, we further explored the binding modes of various types of inhibitors to CYP2D6 using a combination of ligand- and protein-based modeling approaches. Firstly, we developed and validated a pharmacophore model for CYP2D6 inhibitors, which consisted of two hydrophobic features and one hydrogen bond acceptor feature. Secondly, we constructed and validated a quantitative structure-activity relationship (QSAR) model for CYP2D6 inhibitors which gave a poor to moderate prediction accuracy. Thirdly, a panel of CYP2D6 inhibitors were subject to molecular docking into the active site of wild-type and mutated CYP2D6 enzyme. We demonstrated that 8 residues in the active site (Leu213, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, and Phe483) played an important role in the binding to the inhibitors via hydrogen bond formation and/or π-π stacking interaction. Apparent changes in the binding modes of the inhibitors have been observed with Phe120Ile, Glu216Asp, Asp301Glu mutations in CYP2D6. Finally, we screened for potential binders/inhibitors from the Chinese herbal medicine Scutellaria baicalensis (Huangqin, Baikal Skullcap) using the established pharmacophore model for CYP2D6 inhibitors and molecular docking approach. Overall, 18 out of 40 compounds from S. baicalensis were mapped to the pharmacophore model of CYP2D6 inhibitors and most herbal compounds from S. baicalensis could be docked into the active site of CYP2D6. Our study has provided insights into the molecular mechanisms of interaction of synthetic and herbal compounds with human CYP2D6 and further benchmarking studies are needed to validate our modeling and virtual screening results.

The 7-oxabicyclo[2.2.1]heptene ring system is a common structural motif in many pharmacologically interesting molecules. We recognized the potential to employ this highly oxygenated and conformationally-restricted scaffold in diversity-oriented synthesis to generate a library of non-chiral but topologically complex compounds. Herein, we report the synthesis and biological evaluation of two 96-member tricyclic libraries containing the oxabicyclo[2.2.1]heptene framework using acetal formation as the key step.

In the post-genomic era, glycomics (the functional study of carbohydrates in living organisms) has come into the forefront of biological research because the interactions of glycoconjugates with proteins not only occur widely in biological processes of cells but also initiate infection of host cells by bacteria and viruses. Microarrays have been reportedly successful in carbohydrate-protein interaction as well as cellular surface glycan profiling. This review provides an overview of recent progress in the development of microarray-based techniques for glycomic studies. The fabrication, application and challenge/bottleneck of glycan/lectin microarrays have been summarized and discussed.

Polyethylene glycol is found to be a nontoxic and recyclable reaction medium for the microwave-assisted, multi-component one-pot reactions of aromatic aldehydes with ethyl-2-cyanoacetate and 1,3-cyclohexanedione or 5,5- dimethyl-1,3-cyclohexanedione in the presence of piperidine. This environmentally friendly microwave protocol offers ease of operation and enables recyclability of reaction medium and synthesis of a variety of substituted tetrahydrobenzo[b]pyran derivatives. It is an efficient, promising, and green synthetic strategy to construct tetrahydrobenzo[b]pyran skeleton.