QSAR of Human Steroid 5α‐Reductase Inhibitors: Where are the differences between isoenzyme type 1 and 2?

Abstract

AbstractQuantitative Structure Activity Relationships have been established for inhibitors of human steroid 5α‐reductase including 6‐azasteroids and non‐steroidal compounds. From the applied descriptors, those related to the molecular geometry, electronic properties, and the electrostatic surface were derived from semi‐empirical AM1 calculations. A chemical reaction as part of the inhibitory action is indicated by the presence of the ionization potential in the descriptor space. Strong similarities between the variables for the prediction of the binding affinity to the type 1 and IC50 values for the type 2 isoform of the 5α‐reductase were observed. The most pronounced differences in the linear regression QSAR equations were found for the descriptors accounting for the hydrogen‐bonding interaction, suggesting a different hydrogen‐bonding pattern in the binding pocket of both isoforms. Furthermore, the topological indices together with the surface related descriptors point towards a lower content of aromatic amino acids in the binding site of the type 2 isoenzyme. Consequences for the design of new inhibitors are discussed.