Current Pharmaceutical Design - Volume 12, Issue 31, 2006

Before a brief overview on the topics in the current issue, feel bound to thank all the Scientists who kindly agreed to participate in this venture with their original contributions to this special issue, and the time and effort they have put into these comprehensive and carefully done reviews surely make the issue original and attractive. We again wish to express our thanks to Professor Atta-ur-Rahman for the invitation and to the Bentham staff for the editorial assistance and to Prof. Pietro Cozzini (Molecular Modelling Laboratory, Department. of General and Inorganic Chemistry, University of Parma, Parma, Italy) for the proofreading of some manuscripts and the critical helpful suggestions given the Authors. Contrary to the previous issues on "Pharmacophore Elucidation & their use in Drugs & Design: Experimental Structures, Conformational Analysis and 3D QSAR", mostly with a computational character we decided to move a bit and invite scientists who use approaches where the conformational problem was not the end point but lies in the black box of a more wider context finally leading to the “drug”. Ideally the issue can be viewed as a kind of drug design cycle where some approaches are employed that do not exclude but can mutually complement each other. The article by Edward Zartler et al. [1] on “Protein NMR as a screening tool in drug discovery” integrates well with both by A. Goldblum et al. [2] on “Computational protein design” and by Walter Huber et al. [3], which reviews on the state of art of the Surface Plasmon Resonance (SPR) technology. Advances in protein manipulation, whether by biological means (labelling) or physical means (NMR), has become prominent within the past ten years and has created a powerful method which is able to observe ligand-target interactions in solution. Protein based NMR methods have the advantage of supplying detailed structural information in addition to readout of binding events. Computational protein design has emerged in recent years as a field that could make a substantial impact on the design of protein drugs. Surface Plasmon Resonance (SPR) technology has widespread applications in many fields of the drug discovery process. Protein/protein interactions can be monitored in real time when working with biopharmaceuticals as well as protein/small analyte interactions during hit finding, secondary screening, lead optimization and lead selection. Equilibrium binding constants, kinetic rate constants and thermodynamic parameters are obtained from such studies that help to understand the mechanism of the binding reactions. This information can be directly used to improve binding. The final “last but not least” article by Gloria Uccello Baretta et al. [4] points out the role of chirality with respect to the therapeutical and regulatory effects of pharmaceutical products that has led to a growing demand for reliable direct methods for monitoring stereoisomeric products. The analysis of enantiorecognition processes involves the detection of enantiomeric species as well as the study of chiral discrimination mechanisms. In both fields Nuclear Magnetic Resonance (NMR) spectroscopy plays a fundamental role, providing several tools, based on the use of suitable chiral auxiliaries, for observing distinct signals of enantiomers and for investigating the complexation phenomena involved in enantiodiscrimination processes. References [1] Zartler ER, Shapiro MJ. Protein NMR-Based Screening in Drug Discovery. Curr Pharm Des 2006; 12(31): 3963-3972. [2] Rosenberg M, Goldblum A. Computational Protein Design: A Novel Path to Future Protein Drugs. Curr Pharm Des 2006; 12(31): 3973-3997. [3] Huber W, Mueller F. Biomolecular Interaction Analysis in Drug Discovery Using Surface Plasmon Resonance Technology. Curr Pharm Des 2006; 12(31): 3999-4021. [4] Uccello-Barretta G, Balzano F, Salvadori P. Enantiodiscrimination by NMR Spectroscopy. Curr Pharm Des 2006;12(31): 4023-4045.

Protein NMR as a screening tool in drug discovery has become prominent within the past ten years. Advances in protein manipulation, whether by biological means (labeling) or physical means (NMR), have created a powerful method that is able to observe ligand-target interactions in solution.

Computational protein design emerges in recent years as a field that could make a substantial impact on the design of protein drugs. It still consists mainly of redesigning parts of a protein sequence for increasing the stability of a given 3-dimensional conformation of a protein, but has already been extended from redesigning core residues to redesigning in all other protein regions, as well as to the design of backbone conformations. More recently, proteins with new binding functions and new enzymes, protein libraries, designs of full folds and of a new protein fold, have been some of the main highlights. The search and the scoring problems are however not fully solved, and many of the design processes should be examined on much larger scales in order to assess their usefulness. We examine some of the basic assumptions in computational protein design, in particular, the separation between sequence and scaffold designs. Among others, we suggest to include more protein residues in computations, to include relevant parts of the backbone, to use appropriate reference states, to produce the proteins and to validate the designs by structural examination of the protein products.

The review gives first an introduction into the basics of surface plasmon resonance technology. The physical principle is shortly discussed followed by a discussion of the experimental details to be considered when using this technology for biomolecular interaction analysis. Based on recent publications it is demonstrated that the technology has widespread applications in many fields of the drug discovery process. Protein/protein interactions can be monitored in real time when working with biopharmaceuticals as well as protein/small analyte interactions during hit finding, secondary screening, lead optimization and lead selection. Equilibrium binding constants, kinetic rate constants and thermodynamic parameters are obtained from such study that helps to understand the mechanism of the binding reactions. This information can be directly used to improve binding properties of a drug candidate.

The analysis of enantiorecognition processes involves the detection of enantiomeric species as well as the study of chiral discrimination mechanisms. In both fields Nuclear Magnetic Resonance (NMR) spectroscopy plays a fundamental role, providing several tools, based on the use of suitable chiral auxiliaries, for observing distinct signals of enantiomers and for investigating the complexation phenomena involved in enantiodiscrimination processes.

Tuberculosis (TB) is a growing international health concern, since it is the leading infectious cause of death in the world today. In particular, the increasing prevalence of multidrug-resistant (MDR)-TB has greatly contributed to the increased difficulties in the control of TB. Because of the global health problems of TB, the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new anti-TB drugs without cross-resistance with known antimycobacterial agents is urgently needed. This article deals with the following areas. First, it briefly reviews some recent findings on the pharmacological status of fluoroquinolones and rifamycin derivatives. Second, it describes other types of new agents, such as oxazolidinones (linezolid, PNU-100480), nitroimidazoles (nitroimidazopyran PA-824, metronidazole), 2-pyridone, riminophenazines and diarylquinolines, which are being developed as anti-TB drugs. In addition, the future development of new antitubercular drugs is briefly discussed according to the potential pharmacological targets. New critical information on the whole genome of Mycobacterium tuberculosis (MTB) was recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets. Using such findings on MTB genome, drug development using quantitative structureactivity relationship may be possible in the near future.

The characterization of the corticotropin-releasing factor (CRF) family of neuroendocrine regulatory peptides, the cloning and pharmacological characterization of two CRF receptor subtypes (CRF1 and CRF2), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress and the potential involvement of the CRF system in different pathophysiological conditions, including functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and psychopathologies such as anxiety/depression. Compelling pre-clinical data showed that brain CRF administration mimics acute stress-induced colonic responses and enhances colorectal distensioninduced visceral pain in rats through CRF1 receptors. Similarly, peripheral CRF reduced the pain threshold to colonic distension and increased colonic motility in humans and rodents. These observations mimic the manifestations of IBS, characterized by abdominal bloating/discomfort and altered bowel habits. Moreover, CRF-CRF1 pathways have been implicated in the development of anxiety/depression. These psychopathologies, together with stressful life events, have high comorbidity with IBS, and are considered significant components of the disease. From these observations, CRF1 receptors have been suggested as a target to treat IBS. Peripherally acting CRF1 antagonists might directly improve IBS symptoms, as related to motility, secretion and immune response. On the other hand, central actions will be beneficial as to prevent the psychopathologies that co-exist with IBS and as a way to modulate the central processing of stress- and visceral painrelated signals. Here, we review the pre-clinical and clinical data supporting these assumptions, and address the efforts done at a pharmaceutical level to develop effective therapies targeting CRF1 receptors for functional gastrointestinal disorders.