The Conformation of 20-Oxopregnane Hormone from Molecular Orbital Calculations and a Consideration of the Cortisol Receptor

Abstract

31olecular orbital calciilatioris have been performed on models representing the D ring and C-17 substituents of progesterone, corticosterone, and cortisol. The preferred conformations of these C-17 side chains have been dediiced from the total energy minima derived from the calculations. The two-carbon side chain a t C-17 was foiind to prefer a conformation in all three models in which tjhe 20-oxo group projects toward the 8 face of the molecule aiid the C-20,'C-21 bond eclipses the C-l7/17aH bond. In the cortisol molecule the intergroup dist,ance between the 20-oxo and the 118-hydroxyl group was calculated to closely approximate the internit,rogen distance previoiisl?; cahilated for histamine. The cortisol intergroiip distance between the 3-oxo and 118-hydroxyl groiip \va* also foiind to approximate the internitrogen distance previously calculated for serotonin. A receptor complimentary patterii for cortisol is presented, baaed oil the calciilatioris, aiid its role as a possible antagonist in the iiiflammatory response is illustrated.

Molecular Orbital Comparison With Conformation of Oxotremorine and a Comparison With the Muscarinic Pattern

“…When the distanFe between any two first-row atoms on opposite rings exceeds 4 A., the two rings are not influential in respect to their preferred conformations. We have justified the assumption that distant atoms do not influence conformation in a recent quantum mechanical discussion (10). This assumption has been used by others (11).…”

A molecular-orbital study of the bond-length variations in lithium polysilicate

“…1). The theor&ical basis for the neglect of even more distant atoms has been discussed by Kier (1968 (Pauling, 1960), and with previously obtained trends for other second, third and fourth-row tetrahedral oxyanions (Tossell & Gibbs, 1978). In fact, when the difference in mean size and overlap population for each tetrahedron in lithium polysilicate is removed from consideration by calculating the deviation of individual d(T-O) and n(T-O) values from their respective averages (Table 2), it is clear that the relation between Ad(T-O) and An(T-O) is the same for both the SiO 4 and LiO 4 groups (Fig.…”

PCILO study of the conformation of 20‐oxopregnane hormones

“…The minimum energy is found for the conformation in which the C(21) -0(21) bond eclipses the C(20)=0 carbonyl. The EHT calculation of Kier [3] also showed the eclipsed form as a stable conformation. But a preferred position of the O(21) -H hydroxyl bond is cis to the C(20) -C(21) bond, not trans as predicted by EHT [3].…”

“…The EHT calculation of Kier [3] also showed the eclipsed form as a stable conformation. But a preferred position of the O(21) -H hydroxyl bond is cis to the C(20) -C(21) bond, not trans as predicted by EHT [3]. In conformation (3a), there is the possibility of forming an intramolecular hydrogen bond.…”

“…Infrared evidence [8] was presented to indicate that the side chain in cortisol contains a weak intramolecular hydrogen bond between the 20-carbonyl group and the 2 1 -hydroxyl. However Kier's EHT calculation [3] predicted that the stable position of the 21-hydroxyl is away from the side of 20-carbonyl eliminating the possibility of the intramolecular hydrogen bond.…”