Ab initio study of the electronic structure of progesterone and related progestins

Abstract

The geometries and electronic structure of progesterone (P), one of the most important steroid hormones, and related compounds i.e. 20α-hydroxy-progesterone (20α-OHP), 20β-hydroxy-progesterone (20β-OHP) and 17α-hydroxy-progesterone (17α-OHP), were established by high-level ab initio methods using the 6-31G ∗ basis set. In this way bond distances, valence angles and dihedral angles were measured. Likewise, total energy, frontier orbitals (i.e. highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO)), dipole moments, electrostatic charges and electrostatic potentials were calculated. Ab initio results for P and 17α-OHP were compared with their crystal data, and showed good agreement between the ab initio level calculations and the crystal structures. However, differences were observed at the D-ring and the acetyl side chain at C17. The energy of progesterone was higher than its derivatives. Electrostatic charges and electronic density surfaces of the progestins showed different patterns according to the stereochemical arrangement of the carbonyl and hydroxyl functional groups at the acetyl C17 chain. In all the molecules the HOMO and LUMO were located between C4 and C5, along with a high electronic density. The direction of the dipole moment vector was similar in all the molecules, directed beneath the A-ring and with the positive pole pointing toward the methyl group at C18. The electrostatic potentials were observed emerging from the oxygens. This distribution of the intermolecular forces may explain to some extent the non-genomic effects of 4-en progestins. Likewise, the location of the frontier orbitals observed in this work agrees with the metabolic mechanism toward 5α and 5β-reduction of the studied hormones.