A KINETIC-ANALYSIS OF THE CONFORMATIONAL FLEXIBILITY OF STEROID-HORMONES

For a set of 10 androgen steroids and estradiol (E-2), the kinetic fea sibility of conformation flexibility of the cyclic moieties was studie d under the constraint of maintaining the B/C trans and C/D trans ring fusion of the natural and biologically active enantiomer. To this end , the conformational energy surface was quantified using the semiempir ical quantum chemical AMI model. The computational analysis included t he location of Conformational transition states with associated barrie rs, and intrinsic reaction coordinate (IRC) calculations to characteri ze the trajectories of the rotations and the relationships of the tran sition states to neighbouring chair and twist conformations. Conformat ional transformations were observed only for the A and B rings except for E-2, which yielded corresponding transformations for the B and C r ing, respectively. Interestingly, the rotation barriers starting from the lowest-energy conformations differed substantially, ranging from b elow 10 kJ/mol for four compounds to 18-20 kJ/mol for another five com pounds. Moreover, chair and twist conformations were found only for st eroids with higher saturated rings, while semichairs and semitwists oc curred for steroids with aromatic or partly unsaturated rings, and B-r ing transformations lead to kinetically unstable conformations with ve ry flat energy minima. Although the rotation barriers for most of the transitions are clearly above the thermal energy (kT) at room temperat ure when evaluated relative to the lowest-energy conformations, the as sociated energy demands are well below the gain in energy from ligand- receptor binding. The results suggest that conformer interconversion a re feasible from both a thermodynamic and kinetic perspective, and sup port previous investigations in which conformer distributions rather t han lowest energy conformations were considered when assessing hormone receptor topography and the biological activity of ligands.