A Kinetic Analysis of the Conformational Flexibility of Steroid Hormones

Abstract

For a set of 10 androgen steroids and estradiol (E 2 ), the kinetic feasibility of conformation¯exibility of the cyclic moieties was studied under the constraint of maintaining the ByC trans and CyD trans ring fusion of the natural and biologically active enantiomer. To this end, the conformational energy surface was quanti®ed using the semiempirical quantum chemical AM1 model. The computational analysis included the location of Conformational transition states with associated barriers, and intrinsic reaction coordinate (IRC) calculations to characterize the trajectories of the rotations and the relationships of the transition states to neighbouring chair and twist conformations. Conformational transformations were observed only for the A and B rings except for E 2 , which yielded corresponding transformations for the B and C ring, respectively. Interestingly, the rotation barriers starting from the lowest-energy conformations differed substantially, ranging from below 10 kJymol for four compounds to 18 ± 20 kJymol for another ®ve compounds. Moreover, chair and twist conformations were found only for steroids with higher saturated rings, while semichairs and semitwists occurred for steroids with aromatic or partly unsaturated rings, and B-ring transformations lead to kinetically unstable conformations with verȳ at energy minima. Although the rotation barriers for most of the transitions are clearly above the thermal energy (kT) at room temperature when evaluated relative to the lowestenergy conformations, the associated energy demands are well below the gain in energy from ligand-receptor binding. The results suggest that conformer interconversion are feasible from both a thermodynamic and kinetic perspective, and support previous investigations in which conformer distributions rather than lowest energy conformations were considered when assessing hormone receptor topography and the biological activity of ligands.

A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy

“…The global minimum 1A shows a 1␣,2␤-half-chair geometry at A ring; its inversion (e.g., 1A → 1C) is quite easier than that of B and C rings as it costs only about 2 kcal/mol; thus, conformations 1C and 1D, presenting the a 1␤,2␣-half-chair geometry at A ring, give a small contribution (about 4%) to the overall population. The energy barrier for A ring inversion was also determined by locating the transition state of the conformational interconversion 1A → 1C and its height was 7.04 kcal/mol at the present level of calculations, a value somewhat higher than the barrier determined at the AM1 level (4.6 kcal/mol) [7]. The C17 side chain can assume two energy minimum orientations, the preferred one, in agreement with literature X-ray, CD, and computational data [14][15][16], with a torsional angle τ S of −32 • , the second one, with τ S of −138 • , about 1 kcal/mol higher in energy (see 1A versus 1B or 1C versus 1D).…”

“…However, the cis fusion between B and C rings in 2 and 3 makes this bicyclic portion of the tetracyclic skeleton a cis-decaline-like fragment which could enhance the flexibility of the entire molecules; in principle, more than one accessible conformation might exist for these two compounds. To our knowledge, no detailed modeling study on 3, as well as on 2 and 4, has been published while the conformational properties of 1 have been thoroughly discussed along the years though the most recent complete study is limited to the semiempirical level of calculations [7] and ab initio or density functional results are limited to the global minimum conformation [8]. Here, we report a comparative conformational study of the four compounds performed through theoretical calculations at the DFT level; in addition, high field NMR experimental data were used to support the results of the calculations.…”

Identification of nonregulated pollutants in north sea‐produced water discharges

“…Quantitative structure‐activity relationship analysis was performed using the COREPA model for human ER binding affinity [15] and the COREPA‐M model for AhR binding affinity [16]. A list of suggested compounds was analyzed in each QSAR, resulting in a probability of receptor binding for each compound.…”

Quantitative structure‐activity relationship models for prediction of estrogen receptor binding affinity of structurally diverse chemicals

“…The rationale for using multiple conformers arises from experimental evidence that the free energy of binding for steroid hormones to receptors is in the range of Ϫ10 to Ϫ20 kcal/mol [43][44][45], which can provide the necessary energy to elevate conformers from the low(est) energy state during binding. Conformers selected within this range of ⌬⌬ are energetically reasonable from a thermodynamic and 0 H f kinetic perspective [36][37][38]46]. Conformers of each chemical are considered to be a statistical ensemble, based on Boltzman's statistics.…”