Structure-based discovery of nonpeptidic small organic compounds to block the T cell response to myelin basic protein.

We have utilized a computational structure-based approach to identify nonpeptidic small organic compounds that bind to a human leukocyte antigen (HLA) DR1301 molecule (HLA-DR1301 or DR1301) and block the presentation of myelin basic protein peptide 152-165 (MBP 152-165) to T cells. A three-dimensional (3D) structure of DR1301 was derived by homology modeling followed by extensive molecular dynamics simulation for structural refinement. Computational structure-based database searching was performed to identify nonpeptidic small-molecule candidates from the National Cancer Institute (NCI) database containing over 150 000 compounds that can effectively interact with the peptide-binding groove of the HLA molecule. By in vitro testing of 106 candidate small molecules, two lead compounds were confirmed to specifically block IL-2 secretion by DR1301-restricted T cells in a dose-dependent and reversible manner. The specificity of blocking DR1301-restricted MBP presentation was further validated in a binding assay using an analogue of the most potent lead compound. Computational docking was performed to predict the three-dimensional binding model of these confirmed small molecule blockers to the DR1301 molecule and to gain structural insight into their interactions. Our results suggest that computational structure-based searching is an effective approach to discover nonpeptidic small organic compounds to block the interaction between DR1301 and T cells. The nonpeptidic small organic compounds identified in this study are useful pharmacological tools to study the interactions between HLA molecules and T cells and a starting point for the development of a novel therapeutic strategy for the treatment of multiple sclerosis (MS) or other immune-related disorders.

Chemical substituent effect on pyridine permeability and mechanistic insight from computational molecular descriptors.

The objective was (1) to evaluate the chemical substituent effect on Caco-2 permeability, using a congeneric series of pyridines, and (2) compare molecular descriptors from a computational chemistry approach against molecular descriptors from the Hansch approach for their abilities to explain the chemical substituent effect on pyridine permeability. The passive permeability of parent pyridine and 14 monosubstituted pyridines were measured across Caco-2 monolayers. Computational chemistry analysis was used to obtain the following molecular descriptions: solvation free energies, solvent accessible surface area, polar surface area, and cavitation energy. Results indicate that the parent pyridine was highly permeable and that chemical substitution was able to reduce pyridine permeability almost 20-fold. The substituent effect on permeability provided the following rank order: 3-COO- < 4-NH2 < 3-CONH2 < 3-Cl < 3-CHO < 3-OH < 3-CH2OH < 3-C6H5 < 3-NH2 < 3-CH2C6H5 < 3-C2H5 < 3-H < 3-CH3 < 3-F < 4-C6H5. This substituent effect was better explained via molecule descriptors from the computational chemistry approach than explained by classic descriptors from Hansch. Computational descriptors indicate that aqueous desolvation, but not membrane partitioning per se, dictated substituent effect on permeability.

Combined ab initio/empirical approach for optimization of Lennard-Jones parameters for polar-neutral compounds.

The study of small functionalized organic molecules in aqueous solution is a useful step toward gaining a basic understanding of the behavior of biomolecular systems in their native aqueous environment. Interest in studying amines and fluorine-substituted compounds has risen from their intrinsic physicochemical properties and their prevalence in biological and pharmaceutical compounds. In the present study, a previously developed approach which optimizes Lennard-Jones (LJ) parameters via the use of rare gas atoms combined with the reproduction of experimental condensed phase properties was extended to polar-neutral compounds. Compounds studied included four amines (ammonia, methylamine, dimethylamine, and trimethylamine) and three fluoroethanes (1-fluoroethane, 1,1-difluoroethane, and 1,1,1-trifluoroethane). The resulting force field yielded heats of vaporization and molecular volumes in excellent agreement with the experiment, with average differences less than 1%. The current amine CHARMM parameters successfully reproduced experimental aqueous solvation data where methylamine is more hydrophilic than ammonia, with hydrophobicity increasing with additional methylation on the nitrogen. For both the amines and fluoroethanes the parabolic relationship of the extent of methylation or fluorination, respectively, to the heats of vaporization were reproduced by the new parameters. The present results are also discussed with respect to the impact of parameterization approach to molecular details obtained from computer simulations and to the unique biological properties of fluorine in pharmaceutical compounds.