Comprehensive Synthesis of Amino Acid-Derived Thiazole Peptidomimetic Analogues to Understand the Enigmatic Drug/Substrate-Binding Site of P-Glycoprotein

J Med Chem. 2018 Feb 8;61(3):834-864. doi: 10.1021/acs.jmedchem.7b01340. Epub 2018 Jan 23.


A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective of understanding the structural requirements of ligands binding to a highly perplexing substrate-binding site of P-glycoprotein (P-gp) and their effect on modulating the ATPase function of the efflux pump. Compound 1, a stimulator of P-gp ATPase activity, was transformed to ATPase inhibitory compounds 39, 53, and 109. The ATPase inhibition by these compounds was predominantly contributed by the presence of a cyclohexyl group in lieu of the 2-aminobenzophenone moiety of 1. The 4,4-difluorocyclohexyl analogues, 53 and 109, inhibited the photolabeling by [125I]-IAAP, with IC50 values of 0.1 and 0.76 μM, respectively. Selected compounds were shown to reverse paclitaxel resistance in HEK293 cells overexpressing P-gp and were selective toward P-gp over CYP3A4. Induced-fit docking highlighted a plausible binding pattern of inhibitory compounds in the putative-binding pocket of P-gp. The current study underscores the stringent requirement by P-gp to bind to chemically similar molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adenosine Triphosphatases / antagonists & inhibitors
  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism
  • Amino Acids / chemistry*
  • Binding Sites / drug effects
  • Chemistry Techniques, Synthetic
  • Humans
  • Molecular Docking Simulation
  • Peptidomimetics / chemical synthesis*
  • Peptidomimetics / chemistry
  • Peptidomimetics / metabolism
  • Peptidomimetics / pharmacology*
  • Protein Conformation
  • Structure-Activity Relationship
  • Thiazoles / chemistry*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amino Acids
  • Peptidomimetics
  • Thiazoles
  • Adenosine Triphosphatases