A Short Note on Interaction Energy Analysis of Nonclassical Antifolates with Pneumocystis carinii Dihydrofolate Reductase

Author(s): Ertan �?�?ahin

The x-ray structure of the Pneumocystis carinii dihydrofolate reductase (DHFR): trimethoprim: NADPH ternary complex obtained from the Protein Databank was used as a structural template to generate models for the following complexes. P. carinii DHFR: piritrexim: NADPH, P. carinii DHFR: epiroprim: NADPH, and P. carinii DHFR: trimetrexate: NADPH. Each of these complexes, including the original trimethoprim complex was then modeled in 60 angstrom cubes of explicit water and minimized to a rms gradient between 1.0 to 3.0 x 10-5 kcal/angstrom. Subsequently, each antifolate structure was subdivided into distinct substructural regions. The minimized complexes were used to calculate interaction energies for each intact antifolate and its corresponding substructural regions with the P. carinii DHFR binding site residues, the DHFR protein, the solvated complex (which consists of P. carinii DHFR, NADPH, and solvent water), solvent water alone, and NADPH. Antifolate substructural regions which contained nitrogen and carbon atoms in an aromatic environment (i. e. the pteridyl, pyridopyrimidinyl, and diaminopyrimidinyl subregions) contributed most to the stability of antifolate interactions, while interaction energies for the hydrocarbon aromatic rings, methoxy, and ethoxy groups were much less stable.