Selectivity analysis of 5-(arylthio)-2,4-diaminoquinazolines as inhibitorsof Candida albicans dihydrofolate reductase by molecular dynamics simulations

A series of 5-(arylthio)-2,4-diaminoquinazolines are known as selective inh ibitors of dihydrofolate reductase (DHFR) from Candida albicans. We have pe rformed docking and molecular dynamics simulations of these inhibitors with C. albicans and human DHFR to understand the basis for selectivity of thes e agents. Study was performed on a selected set of 10 compounds with variat ion in structure and activity. Molecular dynamics simulations were performe d at 300 K for 45 ps with equilibration for 10 ps. Trajectory data was anal yzed on the basis of hydrogen bond interactions, energy of binding and conf ormational energy difference. The results indicate that hydrogen bonds form ed between the compound and the active site residues are responsible for in hibition and higher potency. The selectivity index, i.e the ratio of I-50 a gainst human DHFR to I-50 against fungal DHFR, is mainly determined by the conformation adapted by the compounds within the active site of two enzymes . Since the human DHFR active site is rigid, the compound is trapped in a h igher energy conformation. This energy difference between the two conformat ions Delta E mainly governs the selectivity against fungal DHFR. The inform ation generated from this analysis of potency and selectivity should be use ful for further work in the area of antifungal research.