Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows

Methods Mol Biol. 2017;1647:221-236. doi: 10.1007/978-1-4939-7201-2_15.


We describe a computational protocol to aid the design of small molecule and peptide drugs that target protein-protein interactions, particularly for anti-cancer therapy. To achieve this goal, we explore multiple strategies, including finding binding hot spots, incorporating chemical similarity and bioactivity data, and sampling similar binding sites from homologous protein complexes. We demonstrate how to combine existing interdisciplinary resources with examples of semi-automated workflows. Finally, we discuss several major problems, including the occurrence of drug-resistant mutations, drug promiscuity, and the design of dual-effect inhibitors.

Keywords: Cancer; Drug resistance mutations; Protein interaction inhibitors; Protein-protein interactions.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Computer Simulation
  • Drug Design*
  • Drug Resistance, Neoplasm
  • Humans
  • Models, Molecular
  • Molecular Targeted Therapy*
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Mapping*
  • Proteins / chemistry*
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism
  • Workflow


  • Antineoplastic Agents
  • Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2