Optimal loading of omecamtiv mecarbil by chitosan: A comprehensive and comparative molecular dynamics study

Abstract

Biodegradable carbohydrate polymers are one of the most efficient material groups applicable in the pharmaceutical industry and medicine. In this research, the effect of chitosan chains, as a natural polymer, on the encapsulation of a myosin activator drug, omecamtiv mecarbil, was investigated by molecular dynamics (MD) simulation. The three main effective factors for loading efficiency including drug concentration (11, 46 and 91%), temperature (298.15 and 318.15 K) and the presence of water molecules (560 molecules) were considered to evaluate the polymer loading efficiency. Based on the results of 12 different systems, since the water molecules provide more effective non-covalent drug interactions than those of chitosan, the presence of molecules decreases the polymer efficiency. To obtain a molecular point of view, all possible mutual radial distribution functions were determined. The interactions between chitosan and omecamtiv mecarbil were reduced at higher temperature and in the presence of water molecules. A comprehensive and comparative insight was also discussed on the role of the three factors in changing the radius of gyration, unbonded energy profile, root-mean-square fluctuations, solvent-accessible surface area and number of hydrogen bonding. Although the same trend was not observed for the effect of drug concentration on all parameters in all systems, the higher temperature and presence of water molecules still decreased the number of loaded drugs on the polymer. Moreover, the aggregation and intra-molecular interaction of chitosan chains were reduced in the presence of water and drug molecules, so that the free active polymer sites were released to form hydrogen bonding interactions among these molecules. As a result, a type of distribution leading to the loading of the drug on polymer was observed.