In silico exploration of binding of selected bisphosphonate derivatives to placental alkaline phosphatase via docking and molecular dynamics

J Mol Graph Model. 2021 Mar:103:107801. doi: 10.1016/j.jmgm.2020.107801. Epub 2020 Nov 16.


Bisphosphonates constitute a group of pyrophosphate analogues therapeutically active against bone diseases. Numerous studies confirm their anticancer and antimetastatic potential as well as ability to relieve pathological pain. Although this is a known class of compounds, many aspects of their action remain unexplained and their new interaction partners are still being discovered. Due to the structural similarity to pyrophosphate, their interaction with pyrophosphate-recognizing enzymes seems to be feasible. In current work, the placental alkaline phosphatase (PLAP) is considered as a potential target for these class of compounds. PLAP is one of the enzymes responsible for degradation of pyrophosphate with high clinical significance. An elevation of PLAP level are considered as a potential cancer marker. An in silico study of complexes formed between selected phosphate derivatives and PLAP was performed. It indicates that all tested compounds: alendronic acid, clodronic acid, etidronic acid, zoledronic acid, imidodiphosphoric acid, pyrophosphoric acid, medronic acid, chloromethylenediphosphonic acid and hypophosphoric acid form a complexes with PLAP, stabilized by hydrogen bonds, hydrophobic and van der Waals interactions. Zoledronic acid, drug used in prevention of bone complications during cancer treatment was found to have the lowest estimated energy of binding (-6.6 kcal/mol). In silico study yielded very low energy of binding also for hypophosphate, equal -6.4 kcal/mol, despite having no identified hydrogen bonds. Subsequent molecular dynamic simulations, followed by molecular mechanics generalized-born surface area with pairwise decomposition calculations confirmed the stability of protein-ligand complexes. The results indicate that selected phosphate derivatives may potentially interact with the enzyme, changing its function, what should be investigated during in vitro studies.

Keywords: Alkaline phosphatase; Bisphosphonate derivatives; MM/GBSA; Molecular docking; Molecular dynamics; Multiple sequence alignment; Zoledronic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase* / chemistry
  • Diphosphonates / chemistry*
  • Female
  • GPI-Linked Proteins
  • Humans
  • Isoenzymes
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • Pregnancy


  • Diphosphonates
  • GPI-Linked Proteins
  • Isoenzymes
  • Alkaline Phosphatase
  • alkaline phosphatase, placental