Current Protein and Peptide Science - Volume 8, Issue 4, 2007

Structure based drug design is a phrase heard nowadays quite frequently among people in the pharmaceutical industry as well as in academic circles. The techniques used in structure determination, both X-ray crystallography and NMR methods, saw rapid advancements causing deposition of huge number of structures in the Protein Databank (PDB). Numerous validation methods and deposition of high resolution structures also made the PDB more reliable for drug designing projects. With time, the designing of drugs using protein/enzyme structures is becoming more automated and robust. To cater to the needs of the drug design process many methods have been developed, using different algorithms, different strategies and different scoring functions. Although many reviews have been published in this area, new methods and protocols have been developed which deserve constant reviewing. Therefore, it was felt that a special issue on structure based drug design is required with a different perspective. In recent years the drug design is routinely done by screening a virtual library of drug-like compounds. Since the number of such compounds has increased in huge numbers, virtual screening using docking methods are practiced. In this issue the review by Romano Kroemer addresses the concepts used in receptor-ligand docking and scoring methods, different approaches and algorithms. He also outlined major challenges involved in structure based design and addressed some of these challenges. Narahari Sastry's group has outlined the virtual screening process with a computational perspective. His group described various computational methods and their relative assessment. In their review Prasad Bharatam's group described the efforts made in the design of selective inhibitors for Glycogen synthase kinase-3, a serine/threonine kinase and a potential drug target for cancer, diabetes and Alzheimer's disease. In their review Matthias Wilmanns and his colleagues outlined the key efforts by the German groups involved in the Mycobacterium tuberculosis structural genomics as a consortium. They highlighted some important potential drug targets involved in metabolic pathways from M. tuberculosis proteome. Finally, I have reviewed the challenges posed by drug targets derived with multiple conformations towards docking as well as virtual screening. I would like to emphasize that this special issue was planned to have a variety of articles addressing different topics in structure based drug design. Structure based design has now grown to a wide extent and these are not the only topics considered in a design project. I believe that I am successful in bringing out a collection of useful reviews for the drug design community. I am very much thankful to all the authors who contributed in this issue and patiently addressed the shortcomings raised by various reviewers. I also thank all the anonymous reviewers who were instrumental in bringing out this issue. I take this opportunity to thank Prof. Ben Dunn, who encouraged me to take up this editorial responsibility and helped me at every stage of the editorial process.

This review gives an introduction into ligand - receptor docking and illustrates the basic underlying concepts. An overview of different approaches and algorithms is provided. Although the application of docking and scoring has led to some remarkable successes, there are still some major challenges ahead, which are outlined here as well. Approaches to address some of these challenges and the latest developments in the area are presented. Some aspects of the assessment of docking program performance are discussed. A number of successful applications of structure-based virtual screening are described.

Virtual screening emerged as an important tool in our quest to access novel drug like compounds. There are a wide range of comparable and contrasting methodological protocols available in screening databases for the lead compounds. The number of methods and software packages which employ the target and ligand based virtual screening are increasing at a rapid pace. However, the general understanding on the applicability and limitations of these methodologies is not emerging as fast as the developments of various methods. Therefore, it is extremely important to compare and contrast various protocols with practical examples to gauge the strength and applicability of various methods. The review provides a comprehensive appraisal on several of the available virtual screening methods to-date. Recent developments of the docking and similarity based methods have been discussed besides the descriptor selection and pharmacophore based searching. The review touches upon the application of statistical, graph theory based methods machine learning tools in virtual screening and combinatorial library design. Finally, several case studies are undertaken where the virtual screening technology has been applied successfully. A critical analysis of these case studies provides a good platform to estimate the applicability of various virtual screening methods in the new lead identification and optimization.

Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase with varied number of actions in cellular signalling systems making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar affective disorders and Alzheimer's disease. Various efforts have produced many potent small molecule inhibitors of GSK-3, which are being tested for modulation of glycogen metabolism, gene transcription, apoptosis and enhancement of insulin-stimulated glucose transport. Majority of the reported inhibitors show their inhibitory effects towards other phylogenetically related kinases also, like cyclin dependant kinases (CDKs). Thus it is important to develop inhibitors that can inhibit GSK-3 selectively. Rational approaches based on the knowledge of the receptor are best suited to address the selectivity problem. Several crystal structures of GSK-3β with different ligands are being reported. These are providing the necessary clues regarding the interaction in the ligand binding domain. Several molecular docking efforts are being taken up to identify the clues for enhancing selectivity towards GSK-3. In this review we present current efforts and future opportunities in designing selective GSK-3 inhibitors.

Tuberculosis has become one of the deadliest global emergencies due to the widespread existence of multiple drug resistance strains of Mycobacterium tuberculosis and the increase of immuno-compromised populations in large parts of the world. Although the complete genome of M. tuberculosis became available in 1998, opening unprecedented opportunities for target-specific drug development, the progress since then has been slow, mainly due to a lack of a sufficiently strong interest by pharmaceutical and biotechnology industries. One of the most promising tools for future drug discovery lies in the elucidation of the molecular structures of potential drug targets from the M. tuberculosis proteome. During the last five years, the structures of about 200 unique targets have already been determined, which comprise about 5% of the entire M. tuberculosis proteome. As an example, we present the approach and some of the key achievements of the X-MTB consortium based in Germany. We summarize and discuss some recent highlights of potential drug targets of M. tuberculosis involved in lipid metabolism, protein phosphorylation/dephosphorylation and amino acid biosynthesis. The achievements of several structural genomics consortia that focus on targets from the M. tuberculosis proteome are now providing a solid framework to support coordinated international approaches for future structure-based drug discovery programs at the interface between industrial enterprises and academic research. One of the objectives will be to focus on target complexes, in addition to single targets that dominate the present repository of structures from the M. tuberculosis proteome.

Structure based drug designing is now a popular technique used for increasing the speed of drug designing process. This was made possible by the availability of many protein structures which helped in developing tools to understand the structure function relationships, automated docking and virtual screening. Knowledge of structure based functional properties of a drug target is very essential for a successful in silico designing of drugs. However, some problems associated with the structure determination process and lack of knowledge of conformational freedom associated with available protein structures are the hurdles involved in structure based drug designing. Docking and virtual screening processes depend on the active site structure of the receptor molecule and subtle differences in the conformations of these molecules due to flexibility pose a serious threat to the drug designing process. In this review problems associated with the conformations of proteins and homology models was reviewed.

In today's research environment, a wealth of experimental/theoretical structural data is available and the number of therapeutically relevant macromolecular structures is growing rapidly. This, coupled with the huge number of small non-peptide potential drug candidates easily available (over 7 million compounds), highlight the need of using computeraided techniques for the efficient identification and optimization of novel hit compounds. Virtual (or in silico) ligand screening based on the three-dimensional structure of macromolecular targets (SB-VLS) is firmly established as an important approach to identify chemical entities that have a high likelihood of binding to a target molecule to elicit desired biological responses. A myriad of free applications and services facilitating the drug discovery process have been posted on the Web. In this review, we cite over 350 URLs that are useful for SB-VLS projects and essentially free for academic groups. We attempt to provide links for in silico ADME/tox prediction tools, compound collections, some ligand-based methods, characterization/simulation of 3D targets and homology modeling tools, druggable pocket predictions, active site comparisons, analysis of macromolecular interfaces, protein docking tools to help identify binding pockets and protein- ligand docking/scoring methods. As such, we aim at providing both, methods pertaining to the field of Structural Bioinformatics (defined here as tools to study macromolecules) and methods pertaining to the field of Chemoinformatics (defined here as tools to make better decisions faster in the arena of drug/lead identification and optimization). We also report several recent success stories using these free computer methods. This review should help readers finding free computer tools useful for their projects. Overall, we are confident that these tools will facilitate rapid and cost-effective identification of new hit compounds. The URLs presented in this review will be updated regularly at www.vls3d.com in the coming months, “Links” section.

The next generation of vaccines are being rationally designed according to rules that govern the way in which antigen is recognised by and stimulates the immune system. Amongst the first cells that encounter potentially dangerous agents such as viruses and bacteria are cells of the innate immune system, such as dendritic cells, that are widely distributed throughout the body including the skin. These cells patrol most tissues and have on their surface an array of receptors that have evolved to recognise many of the surface features of pathogens including the lipids and carbohydrates of structural lipoproteins, glycolipids and glycoproteins. Once encountered, recognised and engaged by a particular receptor on the dendritic cell, pathogenic material may then be transported inside the cell and processed for presentation to cells of the adaptive immune system. The result of this concert of events is a specific cellular or antibody response to particular epitopes of the invading pathogen. If then ways can be found to specifically target dendritic cells, through their specific receptors, then the efficacy and potency of vaccines could well be greatly improved. This review covers some of the approaches that we and others are pursuing in order to achieve this result.