Computational Studies Identifying Entry Inhibitor Scaffolds Targeting the Phe43 Cavity of HIV-1 gp120

Cristina Tintori, Manikandan Selvaraj, Roger Badia, Bonaventura Clotet, José A. Esté, Maurizio Botta

Research output: Contribution to journalArticleResearchpeer-review

10 Citations (Scopus)


Targeting protein-protein interactions, such as the HIV-1 gp120-CD4 interface, has become a cutting-edge approach in the current drug discovery scenario. Many small molecules have been developed so far as inhibitors of the interaction between CD4 and HIV-1 gp120. However, due to a variety of reasons such as solubility, drug toxicity and drug resistance, these inhibitors have failed to prove clinically useful. As such, the identification of novel compounds that bind to protein-protein interactions is still a research area of considerable interest. Here, a structure-based virtual screening approach was successfully applied with the aim of identifying novel HIV-1 entry inhibitors targeting the Phe43 pocket of HIV-1 gp120. Several compounds able to inhibit viral replication in cell culture were identified, with the best agent endowed with an EC50value of 0.9μM. Inactivity of all the identified hits toward a mutant (Met475Ile) strain strongly suggests that they interact in the Phe43 cavity of gp120, as intended. Remarkably, all of these small molecules have a chemical scaffold unrelated to any known class of entry inhibitors reported thus far. Overall, our strategy led to the identification of four novel chemical scaffolds that inhibit HIV-1 replication through the destabilization of the HIV-1 gp120-CD4 interface. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Original languageEnglish
Pages (from-to)475-483
Issue number3
Publication statusPublished - 1 Mar 2013


  • Gp120-CD4
  • HIV-1
  • Phe43 cavity
  • Protein-protein interactions
  • Virtual screening


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