N. S. Alekseeva, T. I. Los’, L. M. Antypenko

Zaporizhzhya State Medical University

Organic and Bioorganic Chemistry Department

Docking studies of the 2-([1,2,4]triazolо[1,5-c]quinazolin-2-ylsulfanyl)acetamides to Candida albicans dihydrofolate reductase

Candida albicans is one of the leading causes among microbial infection in the hospital setting, and opportunistic fungal infections present a major problem to AIDS patients. One of the ways to develop new therapeutically useful agents against fungal growth is synthesis of dihydrofolate reductase (DHFR) inhibitors. [1] Assuming the fact, that 7-(pentan-3-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine is reported to has affinity to DHFR and structurally resembles synthesized 2-([1,2,4]triazolо[1,5-c]-quinazolin-2-ylsulfanyl)acetamides; and also because broad spectrum antibiotic trimethoprimt has a striking selectivity for DHFR, docking studies of above mentioned triazoloquinazolines could predict the possibility of antimicrobial and antifungal activity presence as well as it’s mechanism.

The structure of all synthesized compounds was confirmed by elemental analysis and their spectral data (FT-IR, LC-MS and ¹H-NMR spectra).

The molecular docking study was performed using geometry optimized structure of the compounds into the active site of DHFR (1AI9 and 1AOE, for the holoenzyme and the inhibited enzyme structure, respectively) [2]. Investigation was conducted by flexible molecular docking using the software package OpenEye [3,4]. The obtained scoring functions (Shapegauss, PLP, Chemgauss2, Chemgauss3, Chemscore, OEChemscore, Screenscore, CGO, CGT, Zapbind, Consensus Score) indicate the best possibility of the matching into the ligand-protein complex. The 7-(pentan-3-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (GW345) was used as the reference [2].

Molecular docking with visual inspection indicated that 2-([1,2,4]triazolo[1,5-c]quinazolin-2-ylthio)-N-(5-(2-(3-chlorophenylamino)-2-oxoethylthio)-1,3,4-thia-diazol-2-yl)acetamide was bound to the DHFR with hydrogen bond: N···NH/ARG 79B (2.50 Å). According to Consensus score it showed the highest affinity to DHFR, but even better comparing with reference compound.

Figure. Interaction of the substance with the binding site of DHFR; H-bond is shown as dotted line

As a result, among investigated 2-([1,2,4]triazolо[1,5-c]quinazolin-2-ylsulfanyl)acetamides there were found substances with high affinity to DHFR. The antifungal activity of the ones with best Consensus Scores will be investigated in vitro.

Literature:

1. X-ray crystallographic studies of Candida albicans dihydrofolate reductase. High resolution structures of the holoenzyme and an inhibited ternary complex. M Whitlow, A J Howard, D Stewart, K D Hardman, L F Kuyper, D P Baccanari, M E Fling, R L Tansik. J. Biol. Chem. 12/1997; 272(48):30289-98.

2. Protein Data Bank, pdb. [http://www.pdb.org].

3. Virtual Screening in Drug Discovery, (Eds.: J. Alvarez, B. Shoichet), CRC Press, Taylor & Francis, Boca Raton, FL, 2005, 451.

4. Fred Receptor2.2.5, Vida4.1.1, Flipper, Babel3, Omega2.4.3 and Fred2.2.5: OpenEye Sci. Soft. Inc. Santa Fe, NM, USA; 2011. [http://www.eyesopen.com].