Ab initio calculations of the electronic structure of glucocorticoids

Glucocorticoids promote the conversion of protein into glucose and glycogen, act as anti-inflammatory and block the immune response. Progesterone may follow two metabolic routes: one to corticosterone and the other to cortisol. Because their biological importance and their interesting metabolism, the geometry and electronic structure, at ab initio level with the 6-31G* basis set, of the following glucocorticoids: deoxycorticosterone (DOC), corticosterone (C), deoxycortisol, cortisol and cortisone, were studied. The precursors progesterone (P) and 17 alpha-hydroxy-progesterone (17 alpha-OHP) were included for comparison. Likewise, the X-ray crystal conformers of all the steroids were submitted to single point calculations with the 6-31G* basis set. Interatomic distances and valence angles were almost similar for all the studied molecules. However, dihedral angles were different in the C/D-ring system. X-ray crystal conformers also showed some differences of the dihedral angles when compared with their respective theoretical molecules. Progesterone showed the highest total energy, followed by DOC and 17 alpha-OHP. The addition of two hydroxyl groups (C and deoxycortisol) lowered still more the total energy but it was almost similar in both steroids. Cortisone was followed by cortisol which showed the lower energy among all the studied molecules. X-ray crystal conformers showed always higher energy than their corresponding theoretical molecules. Cortisol showed also the higher HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energies followed by 17 alpha-OHP, P, deoxycortisol, C, DOC and cortisone. This sequence was similar for both HOMO and LUMO energy values. In all the cases both HOMO and LUMO were located along the pi-double bond between C4 and C5, including also C6 and the carbonyl at C3. Dipole moments were larger for the compounds bearing the 17 alpha-hydroxy functional group, i.e. 17 alpha-OHP, deoxycortisol, cortisol and cortisone. The electrostatic potentials were associated directly with the lone pairs of oxygen atoms of the hydroxyl and carbonyl functional groups. By the results it is concluded that the 17 alpha-hydroxy functional group enhances the dipole moment and elicit an extra electrostatic potential increasing the glucocorticoid action. Besides, this functional group might be important for receptor-glucocorticoid recognition and genomic interaction. (C) 1998 Elsevier Science B.V. All rights reserved.