An Approach for Zika Virus Inhibition Using Homology Structure of the Envelope Protein.
To find an effective drug for Zika virus, it is important to understand how numerous proteins which are critical for the virus' structure and function interact with their counterparts. One approach to inhibiting the flavivirus is to deter its ability to bind onto glycoproteins; however, the crystal structures of envelope proteins of the ever-evolving viral strains that decipher glycosidic or drug-molecular interactions are not always available. To fill this gap, we are reporting a holistic, simulation-based approach to predict compounds that will inhibit ligand binding onto a structurally unresolved protein, in this case the Zika virus envelope protein (ZVEP), by developing a three-dimensional general structure and analyzing sites at which ligands and small drug-like molecules interact. By examining how glycan molecules and small-molecule probes interact with a freshly resolved ZVEP homology model, we report the susceptibility of ZVEP to inhibition via two small molecules, ZINC33683341 and ZINC49605556-by preferentially binding onto the primary receptor responsible for the virus' virulence. Antiviral activity was confirmed when ZINC33683341 was tested in cell culture. We anticipate the results to be a starting point for drug discovery targeting Zika virus and other emerging pathogens.
Biological Engineering, Texas A&M University, 303C Scoates Hall, 2117 TAMU, College Station, TX, 77843, USA. sfernando@tamu.edu.
Sandun
http://orcid.org/0000-0002-7692-2170
S
Fernando
Biological Engineering, Texas A&M University, 303C Scoates Hall, 2117 TAMU, College Station, TX, 77843, USA.
Teshan
T
Fernando
Department of Virology, Veterinary Research Institute, Hudcova 70, 62100, Brno, Czech Republic.
Michal
M
Stefanik
Department of Virology, Veterinary Research Institute, Hudcova 70, 62100, Brno, Czech Republic.|Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, 37005, Ceske Budejovice, Czech Republic.
Ludek
L
Eyer
Department of Virology, Veterinary Research Institute, Hudcova 70, 62100, Brno, Czech Republic.|Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, 37005, Ceske Budejovice, Czech Republic.
Daniel
D
Ruzek
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D008958:Models, Molecular; D011134:Polysaccharides / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D019562:Viral Load / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects / Q000378:metabolism*
D000998:Antiviral Agents; D011134:Polysaccharides; D054852:Small Molecule Libraries; D014759:Viral Envelope Proteins
Drug discovery; Druggability; Homology model; Zika virus
Arch Virol. 2007;152(4):687-96
17195954
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D201-5
15608177
J Comput Biol. 2000 Feb-Apr;7(1-2):203-14
10890397
JAMA. 2016 Mar 1;315(9):865-6
26818622
J Biol Chem. 2004 Sep 10;279(37):38755-61
15190071
Travel Med Infect Dis. 2016 Jan-Feb;14 (1):52-4
26748604
Nucleic Acids Res. 2014 Jul;42(Web Server issue):W252-8
24782522
J Comput Chem. 2005 Dec;26(16):1781-802
16222654
PLoS Negl Trop Dis. 2016 May 10;10 (5):e0004695
27163257
J Infect Dis. 2016 Sep 1;214(5):707-11
27234417
J Chem Theory Comput. 2012 Jul 10;8(7):2435-2447
22798729
BMJ. 2016 Jan 29;352:i595
26825803