TY - GEN
T1 - Inhibition of Primed Ebola Virus Glycoprotein by Peptide Compound Conjugated to HIV-1 Tat Peptide Through a Virtual Screening Approach
AU - Alkaff, Ahmad Husein
AU - Saragih, Mutiara
AU - Nasution, Mochammad Arfin Fardiansyah
AU - Tambunan, Usman Sumo Friend
N1 - Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - A higher prevalence of Ebola hemorrhagic fever is caused by Ebola virus (EBOV). It enters into the host cell through macropinocytosis mechanism. During the entry process, the primed viral glycoprotein (GPcl) interacts with a lysosomal cholesterol transporter, Niemann Pick C1 (NPC1), leading to the fusion of the viral envelope and the host endosomal membrane. Hence, disrupting the interaction between EBOV GPcl and host NPC1 is a promising way to prevent the viral nucleocapsid content entering the cytoplasm. In this study, a virtual screening approach has been used to investigate peptide compounds conjugated to HIV-1 Tat peptide as drug lead candidate inhibiting EBOV GPcl. About 50,261 peptides from NCBI PubChem database, which acts as ligands, were subjected to initial toxicological screening to omit ligands with undesired properties. The remaining ligands underwent a pharmacophore search, rigid docking, and flexible docking simulation to discover ligands with favorable inhibition activities. Calfluxin, SNF 8906, grgesy, phosphoramidon, and endothelin (16-21) were five ligands which have lower ΔGbinding value compared to the standard ligand. The chosen ligands were subjected to absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) analysis, which was accomplished by pkCSM software. Subsequently, they were conjugated to HIV-1 Tat peptide to accumulate them inside the endosome. The inhibition activity was reevaluated by the second flexible molecular docking simulation. As a result, only C-Calfluxin showed improved affinity while managing minimal conformational changes in protein-peptide interaction compared to its respective unconjugated ligand.
AB - A higher prevalence of Ebola hemorrhagic fever is caused by Ebola virus (EBOV). It enters into the host cell through macropinocytosis mechanism. During the entry process, the primed viral glycoprotein (GPcl) interacts with a lysosomal cholesterol transporter, Niemann Pick C1 (NPC1), leading to the fusion of the viral envelope and the host endosomal membrane. Hence, disrupting the interaction between EBOV GPcl and host NPC1 is a promising way to prevent the viral nucleocapsid content entering the cytoplasm. In this study, a virtual screening approach has been used to investigate peptide compounds conjugated to HIV-1 Tat peptide as drug lead candidate inhibiting EBOV GPcl. About 50,261 peptides from NCBI PubChem database, which acts as ligands, were subjected to initial toxicological screening to omit ligands with undesired properties. The remaining ligands underwent a pharmacophore search, rigid docking, and flexible docking simulation to discover ligands with favorable inhibition activities. Calfluxin, SNF 8906, grgesy, phosphoramidon, and endothelin (16-21) were five ligands which have lower ΔGbinding value compared to the standard ligand. The chosen ligands were subjected to absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) analysis, which was accomplished by pkCSM software. Subsequently, they were conjugated to HIV-1 Tat peptide to accumulate them inside the endosome. The inhibition activity was reevaluated by the second flexible molecular docking simulation. As a result, only C-Calfluxin showed improved affinity while managing minimal conformational changes in protein-peptide interaction compared to its respective unconjugated ligand.
KW - Ebola
KW - Flexible molecular docking simulation
KW - GPcl
KW - HIV-1 Tat
KW - NPC1
KW - Peptide
KW - Virtual pharmacophore screening
UR - http://www.scopus.com/inward/record.url?scp=85082115126&partnerID=8YFLogxK
U2 - 10.1007/978-3-030-34585-3_14
DO - 10.1007/978-3-030-34585-3_14
M3 - Conference contribution
AN - SCOPUS:85082115126
SN - 9783030345846
T3 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
SP - 153
EP - 165
BT - Computational Intelligence Methods for Bioinformatics and Biostatistics - 15th International Meeting, CIBB 2018, Revised Selected Papers
A2 - Raposo, Maria
A2 - Ribeiro, Paulo
A2 - Sério, Susana
A2 - Staiano, Antonino
A2 - Ciaramella, Angelo
PB - Springer
T2 - 15th International Conference on Computational Intelligence Methods for Bioinformatics and Biostatistics, CIBB 2018
Y2 - 6 September 2018 through 8 September 2018
ER -
