Small molecule inhibitors of HIVgp41 N-heptad repeat trimer formation.
Bioorg Med Chem Lett
; 25(14): 2853-9, 2015 Jul 15.
Article
in En
| MEDLINE
| ID: mdl-26013847
Identification of mechanistically novel anti-HIV fusion inhibitors was accomplished using a computer-aided structure-based design approach with the goal of blocking the formation of the N-heptad repeat (NHR) trimer of the viral protein gp41. A virtual screening strategy that included per-residue interaction patterns (footprints) was employed to identify small molecules compatible with putative binding pockets at the internal interface of the NHR helices at the core native viral six-helix bundle. From a screen of â¼2.8 million compounds using the DOCK program, 120 with favorable energetic and footprint overlap characteristics were purchased and experimentally tested leading to two compounds with favorable cell-cell fusion (IC50) and cytotoxicity profiles. Importantly, both hits were identified on the basis of scores containing footprint overlap terms and would not have been identified using the standard DOCK energy function alone. To our knowledge, these compounds represent the first reported small molecules that inhibit viral entry via the proposed NHR-trimer obstruction mechanism.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
HIV Envelope Protein gp41
/
HIV-1
/
HIV Fusion Inhibitors
/
Small Molecule Libraries
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem Lett
Year:
2015
Document type:
Article