The Institute has implemented an effective interdisciplinary strategy for the design of diverse families of bioactive agents. It is based on a synergistic partnership between computational chemistry and experimental pharmacology that allows more rapid and effective design of new bioactive agents. It can be adapted to apply to different degrees of knowledge of the mechanisms of action and to many types of active systems. This strategy is currently being used for the design of CNS active therapeutic agents, particularly opioid analgesics without side-effects, novel analgesics, cognitive enhancers, and the design of peptidomimetics.
The Institute is currently developing robust protocols for construction of 3D models of proteins. These strategies include: i) construction of 3D models of globular proteins from templates by homology modeling and ii) construction of 3D models of integral membrane bound proteins without a template using a sequence divergence analysis method developed at MRI. This capability has a positive impact on both the design of bioactive agents and the assessment of their adverse effects because it allows explicit modeling of these agents with proteins related to their mechanism of actin. These methods are currently being used to construct 3D models of two families of metabolizing heme proteins, peroxidases, and cytochrome P450s. They are also being used to construct 3D models of membrane bound G-Protein coupled receptors.
The Institute is using state-of-the-art methods, including energy minimization and molecular dynamic simulations to characterize ligand-protein interactions. These methods can be used for structure-based inhibitor design, identification of determinants of enzyme efficacy, of substrate and product specificity, and computer-aided protein engineering, i.e. the relationship between protein structure and function and the effect of mutations on them.
The Institute has developed effective strategies for mechanistic computer-assisted risk assessment that can be used for a variety of adverse effects. These strategies involve: i) evaluation of toxic product formation by chemical and biochemical transformations of the parent compound; ii) modeling of interactions of putative toxic agents with their target biomacromolecules; iii) determination of the properties leading to the toxic response; and iv) use of these properties to screen untested compounds for toxicity. Specifically, such protocols have been used for the evaluation of chemicals as potential carcinogens, teratogens, and toxic agents.