Research Trends

Several new disciplines of research have developed into drug discovery modules including genomics, bioinformatics, proteomics, microarray plans, and others to give the drug discovery groups newer tools to secure lead compounds. What follows are some of the current topics of research in drug discovery. Generally, a good assessment of these trends would be found in journals like Nature Reviews Drug Discovery (6).

Computer-assisted drug design (CADD), also called computer-assisted molecular design (CAMD), represents more recent applications of computers as tools in the drug design process, though it does not replace the human element in analyzing the data.

In considering this topic, it is important to emphasize that computers cannot substitute for a clear understanding of the system being studied. That is, a computer is only an additional tool to gain better insight into the chemistry and biology of the problem at hand.

Once potential drug designs have been identified by the methods described earlier, other molecular modeling techniques may then be applied. For example, geometric optimization may be used to "relax" the structures and to identify low-energy orientations of drugs in receptor sites. Molecular dynamics may assist in exploring the energy landscape, and free energy simulations can be used to compute the relative binding of free energies of a series of putative drugs. Many of these tools are available at the National Institutes of Health website (7).

In vitro screening for drugs that inhibit cytochrome P450 enzymes is well established as a means of predicting potential metabolism-mediated drug interactions in vivo. Given that these predictions are based on enzyme kinetic parameters observed from in vitro experiments, the miscalculation of the inhibitory potency of a compound can lead to an inaccurate prediction of an in vivo drug interaction, potentially preventing a safe drug from advancing in development or allowing a potent inhibitor to "slip" into the patient population. The processes that underlie the generation of in vitro drug metabolism data, and commonly encountered uncertainties and sources of bias and error that can affect extrapolation of drug-drug interaction information to the clinical setting, offer remarkable drug discovery opportunities.

Carbohydrates present both potential and problems—their biological relevance has been recognized, but problems in procuring sugars rendered them a difficult class of compounds to handle in drug discovery efforts. The development of the first automated solid-phase oligosaccharide synthesizer and other methods to rapidly assemble defined oligosaccharides have fundamentally altered this situation. There are now opportunities for the development of carbohydrate-based vaccines, defined heparin oligosaccharides, and aminoglycosides that have recently begun to influence drug discovery.

New perspectives on the complexity of G-protein-coupled receptor (GPCR) signaling and the increased resolution of existing tools for studying GPCR behavior has led to the conception of new hypotheses that affect the discovery of drugs acting at GPCRs. The novel concepts of collateral efficacy and permissive antagonism in the search for synthetic agonists and antagonists, respectively, will be essential in the search for drugs with unique therapeutic profiles. These concepts have been applied to design drugs against HIV as an example of how such concepts might be taken into consideration for GPCR-targeted drugs in general.

The phenomenon of multidrug efflux, whereby a single transporter is capable of recognizing and transporting multiple drugs with no apparent common structural similarity, was first described in higher eukaryotes where P-glycoprotein was found to provide resistance to anticancer chemotherapeutic agents via an adenosine triphosphate (ATP)-driven efflux process. In the late 1980s and early 1990s, it became apparent that multidrug efflux systems were also present in microorganisms, with the identification of bacterial multidrug transporters such as Bmr from Bacillus subtilis, QacA from Staphylococcus aureus, and EmrB from Escherichia coli. Since that time, the number of characterized multidrug efflux transporters has expanded dramatically, and it appears from genomic analyses that multidrug efflux systems are probably essentially ubiquitous.

Several disciplines of research have emerged to create remarkable new opportunities for drug development. Some important ones are described in the following sections.

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