2. Academic Validation
  3. Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements

Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements

  • Eur J Med Chem. 2021 Nov 15:224:113681. doi: 10.1016/j.ejmech.2021.113681.
Ildar R Iusupov 1,  Francesca Curreli 2,  Evgeniy A Spiridonov 1,  Pavel O Markov 1,  Shahad Ahmed 2,  Dmitry S Belov 1,  Ekaterina V Manasova 1,  Andrea Altieri 3,  Alexander V Kurkin 4,  Asim K Debnath 5
Affiliations

Affiliations

  • 1 EDASA Scientific, Scientific Campus, Moscow State University, Leninskie Gory Bld. 75, 77-101b, Moscow, 119992, Russia.
  • 2 Laboratory of Molecular Modeling & Drug Design, Lindsley F. Kimball Research Institute, New York Blood Center, 310 E 67th Street, New York, 10065, New York, United States.
  • 3 EDASA Scientific, Scientific Campus, Moscow State University, Leninskie Gory Bld. 75, 77-101b, Moscow, 119992, Russia. Electronic address: aaltieri@edasascientific.com.
  • 4 EDASA Scientific, Scientific Campus, Moscow State University, Leninskie Gory Bld. 75, 77-101b, Moscow, 119992, Russia. Electronic address: kurkin@edasascinetific.com.
  • 5 Laboratory of Molecular Modeling & Drug Design, Lindsley F. Kimball Research Institute, New York Blood Center, 310 E 67th Street, New York, 10065, New York, United States. Electronic address: adebnath@nybc.org.
PMID: 34246921 DOI: 10.1016/j.ejmech.2021.113681
Abstract

We present the development of alternative scaffolds and validation of their synthetic pathways as a tool for the exploration of new HIV gp120 inhibitors based on the recently discovered inhibitor of this class, NBD-14136. The new synthetic routes were based on isosteric replacements of the amine and acid precursors required for the synthesis of NBD-14136, guided by molecular modeling and chemical feasibility analysis. To ensure that these synthetic tools and new scaffolds had the potential for further exploration, we eventually tested few representative compounds from each newly designed scaffold against the gp120 inhibition assay and cell viability assays.

Keywords

Drug discovery; HIV; Lead optimization; Screening; Synthesis; gp120.

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