Rational drug design is a systematic approach to drug development which offers the potential for significant savings in time and resources as compared to traditional approaches. Essential for the extension of rational drug design beyond its current level of applicability is an understanding, at an atomic level of detail, of the relationship between drug structure and biological faction. Of particular interest are halogen containing substituents, which are ubiquitous in modern drug therapy. The proposed study will combine state of the art theoretical approaches based on empirical force field calculations to 1) create a database of the free energy contributions of chemical substituents to aqueous solvation and lipid solubility and 2) understand the influence of halogens on the conformational and solubility properties of sugars in nucleoside based therapeutic agents. The proposed work will develop parameters for halogens, allowing for their use in empirical force field calculations. Parameter optimization procedures will include novel approaches to account for parameter correlation problems in the lennard-Jones term. Those parameters will be used to generate the halogen free energy database, which will be comprised of free energy contributions of halogen containing substituents to aqueous solvation and lipid solubility determined via free energy perturbation calculations. The database will allow the medicinal chemist to rationally select substituents for incorporation into a molecule to optimize drug bioavailability. Verification of the free energy database will be performed by using the halogen free energy contributions to calculate partition coefficients for comparison with available experimental data. Long term collaborative efforts will focus on correlations between the free energy data and experimental information on absorption and disposition properties of compounds in the database. The halogen parameters will also be applied to study the influence of halogens on sugar moieties in nucleosides with potential as therapeutic agents. These studies will be performed on the compounds as nucleosides, nucleotides and when incorporated into duplex DNA. Compounds in this class include antiHIV and antinucleoside agents. An example is Gemcitabine, an antineoplastic agent that has been shown to be effective against a variety of cancers, including solid tumors, and to function following incorporation into duplex DNA. The information gained from the proposed study will facilitate the systematic addition of halogens to drug molecules in general and yield an atomic understanding of the role of halogens on the conformational and solubility properties of nucleoside based therapeutic agents, leading to the prediction and development of novel therapeutic compounds.
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