TY - JOUR
T1 - Modification of S-Adenosyl-l-Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation
AU - Tambunan, Usman Sumo Friend
AU - Nasution, Mochammad Arfin Fardiansyah
AU - Azhima, Fauziah
AU - Parikesit, Arli Aditya
AU - Toepak, Erwin Prasetya
AU - Idrus, Syarifuddin
AU - Kerami, Djati
N1 - Funding Information:
FuNDINg: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Publication of this article was funded by the Directorate of Research and Community Engagement of Universitas Indonesia (DRPM UI) through Penelitian Unggulan Perguruan Tinggi (PUPT) 2016 (grant number: 1713/UN2.R12/HKP.05.00/2016).
Publisher Copyright:
© 2017, © The Author(s) 2017.
PY - 2017/4/19
Y1 - 2017/4/19
N2 - Dengue fever is still a major threat worldwide, approximately threatening two-fifths of the world’s population in tropical and subtropical countries. Nonstructural protein 5 (NS5) methyltransferase enzyme plays a vital role in the process of messenger RNA capping of dengue by transferring methyl groups from S-adenosyl-l-methionine to N7 atom of the guanine bases of RNA and the RNA ribose group of 2′OH, resulting in S-adenosyl-l-homocysteine (SAH). The modification of SAH compound was screened using molecular docking and molecular dynamics simulation, along with computational ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) test. The 2 simulations were performed using Molecular Operating Environment (MOE) 2008.10 software, whereas the ADME-Tox test was performed using various software. The modification of SAH compound was done using several functional groups that possess different polarities and properties, resulting in 3460 ligands to be docked. After conducting docking simulation, we earned 3 best ligands (SAH-M331, SAH-M2696, and SAH-M1356) based on ΔGbinding and molecular interactions, which show better results than the standard ligands. Moreover, the results of molecular dynamics simulation show that the best ligands are still able to maintain the active site residue interaction with the binding site until the end of the simulation. After a series of molecular docking and molecular dynamics simulation were performed, we concluded that SAH-M1356 ligand is the most potential SAH-based compound to inhibit NS5 methyltransferase enzyme for treating dengue fever.
AB - Dengue fever is still a major threat worldwide, approximately threatening two-fifths of the world’s population in tropical and subtropical countries. Nonstructural protein 5 (NS5) methyltransferase enzyme plays a vital role in the process of messenger RNA capping of dengue by transferring methyl groups from S-adenosyl-l-methionine to N7 atom of the guanine bases of RNA and the RNA ribose group of 2′OH, resulting in S-adenosyl-l-homocysteine (SAH). The modification of SAH compound was screened using molecular docking and molecular dynamics simulation, along with computational ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) test. The 2 simulations were performed using Molecular Operating Environment (MOE) 2008.10 software, whereas the ADME-Tox test was performed using various software. The modification of SAH compound was done using several functional groups that possess different polarities and properties, resulting in 3460 ligands to be docked. After conducting docking simulation, we earned 3 best ligands (SAH-M331, SAH-M2696, and SAH-M1356) based on ΔGbinding and molecular interactions, which show better results than the standard ligands. Moreover, the results of molecular dynamics simulation show that the best ligands are still able to maintain the active site residue interaction with the binding site until the end of the simulation. After a series of molecular docking and molecular dynamics simulation were performed, we concluded that SAH-M1356 ligand is the most potential SAH-based compound to inhibit NS5 methyltransferase enzyme for treating dengue fever.
KW - NS5 methyltransferase
KW - S-adenosyl-l-homocysteine (SAH)
KW - dengue virus (DENV)
KW - drug design
KW - molecular docking
KW - molecular dynamics
UR - http://www.scopus.com/inward/record.url?scp=85044606619&partnerID=8YFLogxK
U2 - 10.1177/1177392817701726
DO - 10.1177/1177392817701726
M3 - Article
AN - SCOPUS:85044606619
SN - 1177-3928
VL - 11
JO - Drug Target Insights
JF - Drug Target Insights
ER -