Identification of xenobiotics interfering with 5α-reductase (SRD5A2) activity

Area of Science:

• Biochemistry
• Pharmacology
• Computational Biology

Background:

• 5α-Dihydroxytestosterone (DHT) is vital for male sexual development, synthesized by steroid 5α-reductase (SRD5A) isoenzymes.
• SRD5A2 is the primary isoform in reproductive organs; its inhibition can cause developmental complications.

Purpose of the Study:

• To establish an in silico/in vitro approach for identifying potential SRD5A2 inhibitors.
• To screen compounds and validate potential inhibitors through enzyme activity assays.

Main Methods:

• Generated minimized SRD5A2 receptor conformational states using molecular dynamics simulations.
• Applied consensus docking and automated binding pose evaluation for virtual screening.
• Validated potential inhibitors using enzyme activity assays and quantum-mechanical calculations.

Main Results:

• Identified MK-0773, an androgen receptor modulator, as a moderate SRD5A2 inhibitor with an IC50 of 1.70 ±0.54μM.
• Quantum-mechanical calculations indicated MK-0773 is not a covalent inhibitor, unlike finasteride.
• The study improved understanding of SRD5A2-ligand interactions.

Conclusions:

• The developed in silico/in vitro approach is effective for identifying novel SRD5A2 inhibitors.
• Findings contribute to understanding SRD5A2 inhibition mechanisms and potential therapeutic strategies.