Exploring protein-protein intermolecular recognition between meprin-α and endogenous protease regulator cystatinC coupled with pharmacophore elucidation

J Biomol Struct Dyn. 2019 Feb;37(2):440-453. doi: 10.1080/07391102.2018.1429311. Epub 2018 Feb 7.

Abstract

Meprins are a group of zinc metalloproteases of the astacin family which play a pivotal role in several physiological and pathologocal diseases. The inhibition of the meprins by various inhibitors, macromolecular and small molecules, is crucial in the control of several diseases. Human cystatinC, an amyloidogenic protein, is reported to be an endogenous inhibitor of meprin-α. In this computational study, we elucidate a rational model for meprinα-cystatinC complex using protein-protein docking. The complex model as well as the unbound form was evaluated by molecular dynamics simulation. A simulation study revealed higher stability of the complex owing to the presence of several interactions. Virtual alanine mutagenesis helps in identifying the hotspots on both proteins. Based on the frequency of occurrence of hotspot amino acids, it was possible to enumerate the important amino acids primarily responsible for protein stability present at the amino-terminal end of cystatin. Finally, pharmacophore elucidation carried out based on the information obtained from a series of small molecular inhibitors against meprin-α can be utilized in future for rational drug design and therapy.

Keywords: cystatin; hotspots; meprins; pharmacophore model; protein–protein docking.

MeSH terms

  • Drug Discovery
  • Enzyme Stability
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Metalloendopeptidases / chemistry*
  • Metalloendopeptidases / metabolism
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Interaction Domains and Motifs*
  • Protein Subunits
  • Reproducibility of Results
  • Structure-Activity Relationship

Substances

  • Ligands
  • Protein Subunits
  • Metalloendopeptidases
  • meprin A
  • astacin