นโยบายงานวิจัย /จรรยาบรรณนักวิจัย /ระดับคุณภาพบทความวิจัยตีพิมพ์ /ระดับคุณภาพผลงานวิชาการ /แหล่งทุน /ดาวน์โหลด /ฐานข้อมูลวิจัย /วิเคราะห์-สังเคราะห์งานวิจัย /ลิขสิทธิ์ /ข่าว


Rational Design of 4-Aminoquinolone Piperidine Amide as Potent DprE1 Inhibitors: Ligand and Structure Based Drug Design Approach (Poster and Proceeding)


Author

-

Chayanin Hanwarinroj1a, Pharit Kamsri2, Naruedon Phusi1, Bunrat Tharat1, Kampanart Chayajaras1,Auradee Punkvang2, Patchareenart Saparpakorn3, Supa Hannongbua3,  Nitima Suttipanta4, Khomson Suttisintong5 and Pornpan Pungpo


Journal

- The 8th Thailand-Japan International Academic Conference 2016

Volume

- 8

Year

- 2016

Publication type

-

Page list

- 106-112

Abstract

   

The decaprenylphosphoryl-D-ribose oxidase (DprE1) of Mycobacterium tuberculosis is vulnerable bacterial targets to develop new anti-tuberculosis agents. This enzyme catalyzes a key epimerization step in the decaprenyl-phosphoryl-d-arabinose (DPA) pathway to develop mycobacterium cell wall.  4-Aminoquinolone piperidine amides were identified as DprE1 inhibitors with slow on rates and long residence times on the enzyme. To develop novel and potent DprE1 inhibitors in a series of 4-aminoquinolone piperidine amides, 3D-QSAR CoMSIA, molecular docking calculations and binding free energy calculation were performed in this work. The CoMSIA model consisting of steric, electrostatic, hydrophobic, hydrogen bond acceptor and hydrogen bond donor field model has less correlation with inhibitory activity (q2 = 0.62). Correlations of calculated docking score and observed inhibitory activity against DprE1 were found. Hydrogen bond interaction between carbonyl group (C=O) of linker of inhibitor interacted with Leu317 backbone was found as the crucial binding interactions.  Moreover, H-pi interaction between Val365 side chain with aminoquinolone ring and pi-pi interaction aminoquinolone ring and FAD cofactor were obtained. This work has contributed to understand the mechanism of action of these 4-aminoquinolone piperidine amides as DprE1 inhibitors and could result of great help for future rational novel anti-tuberculosis drug design


Keywords

   

 4-Aminoquinolone piperidine amides, 3D-QSAR, Molecular docking and binding free energy.