Molecular modelling approaches in Parkinson’s disease: enhancing Domperidone oral availability through nanopolymers.

Abstract

Parkinson’s disease is symbolized by resting tremor, rigidity, and bradykinesia caused by the loss of dopaminergic neurons in the substantia nigra, the presence of Lewy bodies, and a decent response to levodopa. However, a domperidone (DOMP) supplement is often necessary to remedy the nausea and vomiting caused by this prodrug and its therapeutic counterparts, namely metoclopramide must be supplemented with domperidone therapy to treat nausea and vomiting. Even though it is potentially the best antiemetic by reason of its unique mechanism of action, this drug presents with low solubility. In addition to a plethora of adverse effects; these shortcomings necessitate the use of polymeric nanoparticles (nano-polymers) to boost the dissolution rates by improving the solubility of DOMP. The resultant enhancement in bioavailability of the active ingredient is envisaged to address the challenge of increase adherence and reduce frequency dosing through controlled release. Therefore, the aim of this study was to employ molecular modelling approaches to rationalize the selection of suitable polymers for use in the production of stable domperidone nanopolymers with enhanced bioavailability. Polymers-combinations were designed and synthesized by collaborators and structures were made available for this study. Docking and binding free energy calculations were carried out for on 12 polymers-DOMP complexes. Results showed stability for all complexes, converging at 20ns over a 50ns simulation. Of the polymer-complexes, the HPMC-PVA-DOMP (25.22 kcal/mol) system showed the most optimal binding free energy based on the intermolecular interactions. This demonstrates favorable affinity of DOMP to the polymer, thus justifying its use in Parkin’s diease therapy. The Molecular modelling tools provided in this study underpin knowledge at a molecular level of DOMPpolymer nanocrystal interactions. This was further substantiated by collaborative experimental studies. This study has contributing immensly to the understanding of nano-polymers toward enhanced therapy against Parkinson’s disease.