Homology modeling and structural analysis of 11β-hydroxysteroid dehydrogenase type 2.

Abstract 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) was homology-modeled by a Boltzmann-weighted randomized modeling procedure, using the X-ray crystal structure of 11βHSD1 (PDB code: 3HFG) as a template. The model exhibited significant 3D similarities to 11βHSD1. The contact energy profiles of the 11βHSD2 model were in good agreement with that of the X-ray structure of 11βHSD1. The secondary structure of the 11βHSD2 model exhibited a central 6-stranded all-parallel β-sheet sandwich-like structure, flanked on both sides by 3-helices. Ramachandran plots revealed that only 1.9% of the amino acid residues were in the disfavored region for 11βHSD2. Furthermore, the ligand-binding site (LBS) volume was calculated to be 845 A 3 , which suggests that the LBS of 11βHSD2 is sufficiently large to contain cofactors and substrates (ligands), such as NAD + and cortisol. The electrostatic analysis revealed that the 11βHSD2 model had a positive potential at the LBS, which indicates that 11βHSD2 possibly attracts negatively charged ligands at the LBS. These results indicate that the model was successfully evaluated and analyzed. Consequently, it is proposed that the 11βHSD2 model in the present study will be suitable for further in silico structure-based de novo antitumor drug designing. To the best of our knowledge, this is the latest report of an accurate 11βHSD2 model to target 11βHSD2 for the development of anticancer drugs.