Structural studies of shikimate dehydrogenase from Bacillus anthracis complexed with cofactor NADP.

Bacillus anthracis has been employed as an agent of bioterrorism, with high mortality, despite anti-microbial treatment, which strongly indicates the need of new drugs to treat anthrax. Shikimate pathway is a seven step biosynthetic route which generates chorismic acid from phosphoenol pyruvate and erythrose-4-phosphate. Chorismic acid is the major branch point in the synthesis of aromatic amino acids, ubiquinone, and secondary metabolites. The shikimate pathway is essential for many pathological organisms, whereas it is absent in mammals. Therefore, these enzymes are potential targets for the development of nontoxic antimicrobial agents and herbicides and have been submitted to intensive structural studies. The forth enzyme of this pathway is responsible for the conversion of dehydroshikimate to shikimate in the presence of NADP. In order to pave the way for structural and functional efforts toward development of new antimicrobials we describe the molecular modeling of shikimate dehydrogenase from Bacillus anthracis complexed with the cofactor NADP. This study was able to identify the main residues of the NADP binding site responsible for ligand affinities. This structural study can be used in the design of more specific drugs against infectious diseases.

Genomic databases and the search of protein targets for protozoan parasites.

The development of databases devoted to biological information opened the possibility to integrate, query and analyze biological data obtained from several sources that otherwise would be scattered through the web. Several issues arise in the handling of biological information, mainly due to the diversity of biological subject matter and the complexity of biological approaches towards phenomena of the living world. The integration of genomic data, three-dimensional structures of proteins, biological activity, and drugs availability allows a system approach to the study of the biology. Here we review the current status of these research efforts to develop genomic databases for protozoan parasites, such as the apicomplexan parasites, Trypanosoma cruzi and Leishmania spp. These databases may help in the discovery and development of new drugs against parasite-mediated diseases.

Protein-drug interaction studies for development of drugs against Plasmodium falciparum.

The study of protein-drug interaction is of pivotal importance to understand the structural features essential for ligand affinity. The explosion of information about protein structures has paved the way to develop structure-based virtual screening approaches. Parasitic protein kinases have been pointed out as potential targets for antiparasitic development. The identification of protein kinases in the Plasmodium falciparum genome has opened the possibility to test new families of inhibitors as potential antimalarial drugs. In addition, other key enzymes which play roles in biosynthetic pathways, such as enoyl reductase and chorismate synthase, can be valuable targets for drug development. This review is focused on these protein targets that may help to materialize new generations of antimalarial drugs.

Molecular modeling as a tool for drug discovery.

With the progression of structural genomics projects, comparative modeling remains an increasingly important method of choice to obtain 3D structure of proteins. It helps to bridge the gap between the available sequence and structure information by providing reliable and accurate protein models. Comparative modeling based on more than 30% sequence identity is now approaching its natural template-based limits and further improvements require the development of effective refinement techniques capable of driving models toward native structure. For difficult targets, for which the most significant progress in recent years has been observed, optimal template selection and alignment accuracy are still the major problems. The past year has seen a maturation of molecular modeling, with an increasing number of comparative studies between established methods becoming possible, together with an explosion of new works especially in the areas of combinatorial chemistry and molecular diversity. To achieve this, knowledge about three-dimensional protein structures is crucial for the understanding of their functional mechanisms, and for a rational drug design. This review described recent progress in molecular modeling methodology.