In silico tools to study molecular targets of neglected diseases: inhibition of TcSir2rp3, an epigenetic enzyme of Trypanosoma cruzi

Adv Protein Chem Struct Biol. 2020:122:203-229. doi: 10.1016/bs.apcsb.2020.04.001. Epub 2020 Jun 25.

Abstract

There is a growing interest to study and address neglected tropical diseases (NTD). To this end, in silico methods can serve as the bridge that connects academy and industry, encouraging the development of future treatments against these diseases. This chapter discusses current challenges in the development of new therapies, available computational methods and successful cases in computer-aided design with particular focus on human trypanosomiasis. Novel targets are also discussed. As a case study, we identify amentoflavone as a potential inhibitor of TcSir2rp3 (sirtuine) from Trypanosoma cruzi (20.03 μM) with a workflow that integrates chemoinformatic approaches, molecular modeling, and theoretical affinity calculations, as well as in vitro assays.

Keywords: Computer-aided drug design; Drug discovery; Drug repurposing; Epigenetics; Neglected diseases; Polypharmacology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biflavonoids / chemistry*
  • Biflavonoids / therapeutic use
  • Chagas Disease* / drug therapy
  • Chagas Disease* / enzymology
  • Computer Simulation*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Protozoan Proteins* / antagonists & inhibitors
  • Protozoan Proteins* / chemistry
  • Sirtuins* / antagonists & inhibitors
  • Sirtuins* / chemistry
  • Trypanocidal Agents / chemistry*
  • Trypanocidal Agents / therapeutic use
  • Trypanosoma cruzi / enzymology*

Substances

  • Biflavonoids
  • Enzyme Inhibitors
  • Protozoan Proteins
  • Trypanocidal Agents
  • amentoflavone
  • Sirtuins