Title:Molecular Docking and Pharmacophore Modeling Studies of Fluorinated Benzamides as Potential CETP Inhibitors
Volume: 13
Issue: 3
Author(s): Reema Abu Khalaf*, Sarah Al-Rawashdeh, Dima Sabbah and Ghassan Abu Sheikha
Affiliation:
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman,Jordan
Keywords:
Cholesteryl ester transfer protein, docking, fluorinated benzamides, hyperlipidemia, inhibitors, molecular
modeling.
Abstract: Background: Hyperlipidemia is one of the most common chronic diseases worldwide.
Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that facilitates the transfer of
cholesteryl ester from the atheroprotective high-density lipoprotein (HDL) to the proatherogenic
low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL).
Methods: In this work, synthesis and characterization of five fluorinated 3-benzylamino benzamides
8a-8c, 13a and 13b that target CETP activity were carried out.
Results: Benzamides 8b and 8a showed the highest CETP inhibitory activities with an IC50 of 0.75
μM and 4.1 μM respectively. It was found that the presence of p-OCF3 group (as in 8a-8c) enhances
CETP inhibitory activity more than p-OCF2CHF2 (as in 13a and 13b) which could be attributed to
the bulkiness of the tetrafluoroethoxy group hindering their proper orientation in the binding domain.
Additionally m-F derivatives were found to have higher activity against CETP than p-F ones leaving
the o-F analogues with the weakest anti-CETP bioactivity.
Conclusion: Ligand-based and structure-based drug design strategies confirm that hydrophobic interaction
mediates ligand/protein complex formation and explains the activity of our verified molecules.
