تحديد فارماكوفور جديد للمثبطات اللاستيرويدية لإنزيم -5 ألفاريدكتاز من النمط الثاني و إيجاد مثبطات جديدة بالاعتماد على الفارماكوفور و المسح الافتراضي و الإرساء الجزيئي

Abstract EN

There are a number of disease where the 5-alpha reductase II (5AR2) enzyme is a therapeutic promising biological target.

There are two isozymes of 5AR, namely types I and II.

Inhibition of 5AR2 prevents conversion of testosterone (T) to dihydrotestosterone (DHT), which plays a main role in many diseases, mainly benign prostate hypertrophy (BPH).

There are only three inhibitors in clinical use, all have steroidal structure.

Identifying new nonsteroidal inhibitors is a great challenge.

In this study, we developed a ligand-based pharmacophore from nonsteroidal 5AR2.

The generated pharmacophore included 10 features mapping Hydrogen-bond acceptors (HBA), hydrophobic regions (H), and Aromatic rings (AR).

The pharmacophore was validated on 152 decoy compounds, then it was utilized to screen databases for retrieving potential hits.

The pharmacophore was imposed on botanical components used to treat BPH, to identify the constituents responsible of activity.

The hit which did not obey the Lipinski’s rule of five was excluded, then, the hits were docked on a homology model of 5AR2.

The proposed pharmacophore features were consistent with previous studies conducted on solely steroidal, or steroidal and non-steroidal inhibitors.

The proposed pharmacophore could identify Dutasteride and epristeride as potent inhibitors.

It also could signify new inhibitors of which two are previously tested on the isolated enzyme.

Divanillyltetrahydrofuran was anticipated to be potential inhibitor among the components of Urtica dioica.

The constructed pharmacophore can be used in screening additional libraries, and is worthy of reducing time to discover novel and potent 5AR2 inhibitors, with enhanced affinity and less side effects.