Flexible docking of an acetoxyethoxymethyl derivative of thiosemicarbazone into three different species of dihydrofolate reductase.

Abstract

Dihydrofolate reductases (DHFR) of human, Candida albicans and E coli were docked with their original ligands of X-ray crystal complex using QXP (Quick eXPlore), a docking program. Conditions to reproduce the crystal structures within the root mean square deviation (rmsd) of 2.00 A were established. Applying these conditions, binding modes and species-specificities of a novel antibacterial compound, N4-(2-acetoxyethoxymethyl)-2-acetylpyridine thiosemicarbazone (AATSC), were studied. As the results, the docking program reproduced the crystal structures with average rmsd of six ligands as 0.91 A ranging from 0.49 to 1.45 A. The interactions including the numbers of hydrogen bonds and hydrophobic interactions were the same as the crystal structures and superposition of the crystal and docked structures almost coincided with each other. For AATSC, the results demonstrated that it could bind to either the substrate or coenzyme sites of DHFR in all three species with different degrees of affinity. It confirms the experimentally determined kinetic behavior of uncompetitive inhibition against either the inhibitor or the coenzyme. The docked AATSC overlapped well with the original ligands and major interactions were consistent with the ones in the crystal complexes. The information generated from this work should be useful for future development of antibacterial and antifungal agents.