Ab initio design of drug carriers for zoledronate guest molecule using phosphonated and sulfonated calix[4]arene and calix[4]resorcinarene host molecules

TL;DR

This study uses ab initio calculations to evaluate the potential of phosphonated and sulfonated calix[4]arene and calix[4]resorcinarene macrocycles as drug carriers for zoledronate, aiming to improve osteoporosis treatment.

Contribution

It provides a computational assessment of host-guest complex formation, highlighting the stability and binding preferences of modified macrocycles with zoledronate.

Findings

Most complexes form spontaneously in aqueous conditions.

Insertion of the P-C-P branch is easier than the heterocycle.

Complexes may be unstable in gaseous states but stable in water.

Abstract

Monomolecular drug carriers based on calix[n]-arenes and -resorcinarenes containing the interior cavity can enhance the affinity and specificity of the osteoporosis inhibitor drug zoledronate (ZOD). In this work we investigate the suitability of nine different calix[4]-arenes and -resorcinarenes based macrocycles as hosts for the ZOD guest molecule by conducting {\it ab initio} density functional theory calculations for structures and energetics of eighteen different host-guest complexes. For the optimized molecular structures of the free, phosphonated, sulfonated calix[4]-arenes and -resorcinarenes, the geometric sizes of their interior cavities are measured and compared with those of the host-guest complexes in order to check the appropriateness for host-guest complex formation. Our calculations of binding energies indicate that in gaseous states some of the complexes might be unstable but in aqueous states almost all of the complexes can be formed spontaneously. Of the two different docking ways, the insertion of ZOD with the \ce{P-C-P} branch into the cavity of host is easier than that with the nitrogen containing heterocycle of ZOD. The work will open a way for developing effective drug delivering systems for the ZOD drug and promote experimentalists to synthesize them.