Current Topics in Medicinal Chemistry - Volume 9, Issue 9, 2009

Structure-based drug design (SBDD) and ligand-based drug design (LBDD) remain the most important strategies in drug discovery, covering a variety of current state of the art approaches. Both drug design technologies involve the integration of a number of independent sciences, providing efficient, effective, and challenging approaches to medicinal chemistry. In this special issue of Current Topics in Medicinal Chemistry, entitled Structure- and Ligand-Based Drug Design, six articles in the broad field of medicinal chemistry were included, with a particular focus on key drug design technologies that have a significant impact for the design and development of new chemical entities, such as: bioinformatics, cheminformatics, QSAR, molecular docking, molecular dynamics, pharmacophores, virtual screening, crystallography, NMR, and so on. Here are the highlights. Andricopulo, Salum & Abraham present a review of the current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization. Examples are described in this review of the use of these modern methods for the identification and design of novel active compounds. Some of the lessons that have been learned about best practices in the application of these important drug design approaches are summarized. Bob Clark's review of the current state of prospective 3D QSAR starts by putting the field in context by way of a bibliographic survey of articles touching upon QSAR and docking in the Journal of Medicinal Chemistry over the last several years. It then provides a tabulation of prospective target- and ligand-based studies in the recent literature - i.e., those in which activity predictions were made and experimentally tested. A comparison of the performance of the various approaches - docking, pharmacophores, shape-based methods and molecular fields - indicates that mixed methods seem to generally be the most successful. Consideration of the common challenges faced by all of the approaches illuminates the roots of such synergies and suggests that combinations of docking with locally trained scoring systems hold particular promise for the future.

Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so the score it receives is biophysically sound. If the correct binding pose is not predicted, a skeptic might well infer that the discovery was serendipitous. Surveying over 15 years of the docking literature, we were surprised to discover how rarely sufficient evidence is presented to establish whether docking actually worked for the right reasons. The paucity of experimental tests of theoretically predicted poses undermines confidence in a technique that has otherwise become widely accepted. Of course, solving a crystal structure is not always possible, and even when it is, it can be a lot of work, and is not readily accessible to all groups. Even when a structure can be determined, investigators may prefer to gloss over an erroneous structural prediction to better focus on their discovery. Still, the absence of a direct test of theory by experiment is a loss for method developers seeking to understand and improve docking methods. We hope this review will motivate investigators to solve structures and compare them with their predictions whenever possible, to advance the field.

A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds.

As drug discovery and development has grown ever riskier and more expensive, interest has increased in using computational tools to identify good candidates more quickly and to avoid investing resources in synthesizing and testing compounds that are not likely to succeed. The most powerful of these tools seek to exploit the connection between the three-dimensional (3D) structure of a molecule and its various biological activities. Two fundamentally different ways of addressing this challenge have arisen over the years: ligand-based methods that seek to identify and exploit similarities between the structures of ligands that are known to bind to a given target; and target-based (docking) methods that seek to identify and exploit complementarities to the binding site itself. The structure-activity relationships involved reflect the interplay of many thermodynamic factors, which makes putting them on any kind of quantitative footing a challenge. The progress being made in coming to grips with that challenge is assessed here through a survey of recently published prospective studies, a review of the underlying problems remaining, and consideration of some ways in which different methods are being combined to improve overall performance.

NMR is one of the most powerful techniques for ligand-biomolecule interaction studies and drug screening and design. There are several methods that are strongly used, including chemical shift perturbation (CSP), saturation transfer difference (STD) and diffusion coefficients. However, one of the most useful and easy to apply NMR parameters in medicinal chemistry studies is the spin-lattice relaxation data, which can be employed to investigate the strength and topology of intermolecular interactions, such as drug-drug, drug-protein, drug-DNA, drug-micelle (or vesicle) and biomolecule-biomolecule interactions. This review deals with the newest applications of T1 in different studies of interest for drug design and evaluation.

Parasitic diseases are amongst the foremost threats to human health and welfare around the world. In tropical and subtropical regions of the world, the consequences of parasitic infections are devastating both in terms of human morbidity and mortality. The current available drugs are limited, ineffective, and require long treatment regimens. To overcome these limitations, the identification of new macromolecular targets and small-molecule modulators is of utmost importance. The advances in genomics and proteomics have prompted drug discovery to move toward more rational strategies. The increasing understanding of the fundamental principles of protein-ligand interactions combined with the availability of compound libraries has facilitated the identification of promising hits and the generation of high quality lead compounds for tropical diseases. This review presents the current progresses and applications of structure-based drug design (SBDD) for the discovery of innovative chemotherapy agents for a variety of parasitic diseases, highlighting the challenges, limitations, and future perspectives in medicinal chemistry.

Steroid nuclear hormone binding receptors (SHRs) are ligand activated transcription factors involved in the regulation of target genes associated with key physiological and developmental processes. As such they are important targets for drug discovery. Crystal structures are now available for all members of the SHR family, however, earlier studies carried out using homology models proved to be quite valuable for understanding the binding of natural ligands and for designing novel therapeutic agents. The maleability of the binding pocket means that the crystal structure of an SHR in complex with one ligand may not suffice to explain the binding interactions of that same target with a different ligand. Consequently, induced fit docking and molecular dynamics are shown to be useful and necessary tools for understanding these receptors.