Insight into the orientational versatility of steroid substrates—a docking and molecular dynamics study of a steroid receptor and steroid monooxygenase

Abstract

Numerous steroids are essential plant, animal, and human hormones. The medical and industrial applications of these hormones require the identification of new synthetic routes, including biotransformations. The metabolic fate of a steroid can be complicated; it may be transformed into a variety of substituted derivatives. This may be because a steroid molecule can adopt several possible orientations in the binding pocket of a receptor or an enzyme. The present study, based on docking and molecular dynamics, shows that it is indeed possible for a steroid molecule to bind to a receptor binding site in two or more orientations (normal, head-to-tail reversed, upside down). Three steroids were considered: progesterone, dehydroepiandrosterone, and 7-oxo-dehydroepiandrosterone. Two proteins were employed as hosts: the human mineralocorticoid receptor and a bacterial Baeyer–Villiger monooxygenase. When the steroids were in nonstandard orientations, the estimated binding strength was found to be only moderately diminished and the network of hydrogen bonds between the steroid and the host was preserved.

Molecular features of steroid-binding antidins and their use for assaying serum progesterone

“…For reference, we also docked the ligand from the crystal structure of the sbAvd-2 (I117Y)–progesterone complex [PDB:5LUR] back into the ligand-binding site and, even in this case, the docking produced varying poses dissimilar to the ligand observed in the crystal structure, indicating the challenge of docking progesterone into Avd-like binding pockets. Interestingly, Panek and coworkers [48] recently reported that progesterone docked into human mineralocorticoid receptor and bacterial monooxygenase in orientation (‘D-ring first’) different from that observed in the crystal structures of these proteins (“A-ring first”).…”

Microbial Modifications of Androstane and Androstene Steroids by Penicillium vinaceum

“…Microbial BVMOs have considerably broad substrate scope, for example the PockeMO can oxidize both a and d rings of the steroidal substrates [ 26 ], and this versatility is related to the structure of substrate binding pocket, able to accept bulky substrates in diverse configurations [ 26 , 27 ]. Such an idea of configurational flexibility of steroid substrates was proposed already in 1967 on the basis of diverse metabolic fates of steroids biotransformed by Aspergillus tamarii cultures [ 28 ].…”