A Kinetic Analysis of the Conformational Flexibility of Steroid Hormones

For a set of 10 androgen steroids and estradiol (E2), 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 E2, 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 very ̄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. Quant. Struct.-Act. Relat., 17 (1998) # WILEY-VCH Verlag GmbH, D-69469 Weinheim 0931-8771/98/0510-0437 $17.50+.50/0 437 A Kinetic Analysis of the Conformational Flexibility of Steroid Hormones QSAR