Computer modeling with the ESFF forcefield of human dihydrofolate reductase ternary complex with NADPH and piritrexim (PTX) inhibitor.

Dihydrofolate Reductase (DHFR, EC 1.5.1.3) plays an important role in human physiology. The blocking of its enzymatic activity is a key element in tre atment of many diseases, including cancer and AIDS related infections. Many useful drugs have been developed to date, however, issues of toxicity and drug resistance make it imperative that new inhibitors of DHFR be designed that have increased selectivity and lower toxicity. In this paper, computer modeling data are presented for the interactions of PTX bound to human DHF R NADPH ternary complex. The commercially available ESFF forcefield from MSI was used to develop a c omputer model of the DHFR, PTX and NADPH complex. Water shell of 6 Angstrom was included. This model has been tested against the X-ray structure and r esults of semiempirical calculations performed for simpler systems. The MD trajectories were generated to check the conformational freedom of the inhi bitor. The binding interactions of PTX in the natural L22F mutation of hDHF R that results in methotrexate resistance, was also studied. These results show that the ESFF forcefield, developed mainly for organomet allic systems, may be effectively used in studies of protein structures.