Potential HIV-1 fusion inhibitors mimicking gp41-specific broadly neutralizing antibody 10E8: In silico discovery and prediction of antiviral potency.
J Bioinform Comput Biol
; 16(2): 1840007, 2018 04.
Article
in En
| MEDLINE
| ID: mdl-29439644
ABSTRACT
An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web-oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations. As a result, eight hits-able to mimic pharmacophore properties of bNAb 10E8 by specific and effective interactions with the MPER region of the HIV-1 protein gp41 were selected as the most probable 10E8-mimetic candidates. Similar to 10E8, the predicted compounds target the critically important residues of a highly conserved hinge region of the MPER peptide that provides a conformational flexibility necessary for its functioning in cell-virus membrane fusion process. In light of the data obtained, the identified small molecules may present promising HIV-1 fusion inhibitor scaffolds for the design of novel potent antiviral drugs.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
HIV Envelope Protein gp41
/
Computational Biology
/
HIV Fusion Inhibitors
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Antibodies, Neutralizing
Type of study:
Prognostic_studies
/
Risk_factors_studies
Language:
En
Journal:
J Bioinform Comput Biol
Year:
2018
Type:
Article