Sains Malaysiana 46(10)(2017): 1865–1875

http://dx.doi.org/10.17576/jsm-2017-4610-25

 

Molecular Docking Studies of Selected Medicinal Drugs as Dengue Virus-2 Protease Inhibitors

(Kajian Mengedok Molekul Dadah Ubatan Terpilih sebagai Perencat Protease Virus-2 Denggi)

 

RUFAIDAH OTHMAN¹, ROZANA OTHMAN², AIDA BAHARUDDIN³, NAGASUNDARA RAMANAN RAMAKRISHNAN⁴, NOORSAADAH ABD RAHMAN⁵, ROHANA YUSOF^6,7 & SAIFUL ANUAR KARSANI^1*

 

¹Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

 

²Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

 

³Department of Biotechnology, Faculty of Science, Lincoln University College, 47301 Petaling Jaya, Selangor Darul Ehsan, Malaysia

 

⁴School of Engineering, Monash University Bandar Sunway, 46150 Bandar Sunway, Selangor Darul Ehsan, Malaysia

 

5Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

 

⁶Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

 

⁷Drug Design and Development Research Group (DDDRG), University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

 

Received: 28 July 2016/Accepted: 20 March 2017

 

ABSTRACT

Dengue is a potentially deadly disease with no effective drug. An in silico molecular docking was performed using Autodock 4.2.6 to investigate the molecular interactions between protease inhibitors, comprising antibiotic derivatives namely doxycycline (3), rolitetracycline (5) and a non-steroidal anti-inflammatory drug (NSAID), meclofenamic acid (4), against the NS2B-NS3 protease from dengue virus-2 (DENV-2). The non-competitive inhibitor (3) showed lower binding energy (-5.15 kcal/mol) than the predicted competitive inhibitors 4 and 5 (-3.64 and -3.21 kcal/mol, respectively). Structural analyses showed compound 3 that bound to a specific allosteric site, interacted with Lys74, a significant amino acid residue bonded to one of the catalytic triad, Asp75. Compounds 4 and 5 showed direct binding with two of the catalytic triad, His51 and Ser135, hence, predicted to be competitive inhibitors.

 

Keywords: Dengue virus-2; docking; inhibitors; NS2B-NS3 protease

 

ABSTRAK

Denggi adalah sejenis penyakit yang boleh membawa maut dan sehingga kini tiada sebarang ubat untuk merawat penyakit tersebut. Mengedok molekul secara in silico menggunakan Autodock 4.2.6 telah dijalankan untuk mengkaji interaksi molekul antara perencat protease yang terdiri daripada derivatif antibiotik iaitu doxycycline (3) dan rolitetracycline (5) dan dadah anti-radang bukan steroid (NSAID), asid meklofenamik (4), terhadap NS2B-NS3 daripada virus denggi-2 (DENV-2). Perencat tidak-kompetitif (3) menunjukkan tenaga ikatan yang lebih rendah (-5.15 kcal/mol) berbanding sebatian 4 dan 5 (masing-masing -3.64 dan -3.21 kcal/mol). Analisis struktur menunjukkan sebatian 3 yang terikat pada kawasan alosterik, berinteraksi dengan Lys74, iaitu residu asid amino yang terikat dengan salah satu daripada residu triad pemangkinan, Asp75. Sebatian 4 dan 5 pula menunjukkan ikatan langsung dengan dua triad pemangkinan iaitu His51 dan Ser135, justeru diramalkan sebagai perencat kompetitif.

 

Kata kunci: Mengedok; NS2B-NS3 protease; perencat; virus denggi-2

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*Corresponding author; email: saifule78@um.edu.my