Computational study of micelle-membrane transfer of small drug molecules

SNIC 2019/3-494


SNIC Medium Compute

Principal Investigator:

Christel Bergström


Uppsala universitet

Start Date:


End Date:


Primary Classification:

30101: Pharmaceutical Sciences

Secondary Classification:

30103: Medicinal Chemistry



Poor aqueous solubility is one of the major problems in the drug delivery field. One of the main questions remaining unanswered is the contribution of micelles and vesicles into the transport of active pharmaceutical ingredients(API) from bulk to the cell membrane surface in gastro-intestinal tract. Competition between enthalpy and entropy make the drug molecules' solubilisation highly dependant on the composition of intestinal fluid in general and specifically on the presence of transporters like micelles. On the one hand encapsulation of APIs can prevent it from aggregating with alike molecules and from further crystallisation. On the other hand once the drug molecule is attached to the surface or entrapped within the transporter, the drugs absorption is also getting limited. The crucial role in this balance is believed to be played by the transfer mechanism, which is not yet clear. Several groups propose various hypothesis to explain the nature of the process. Some state the micelle falls apart in the vicinity of the membrane surface, others propose endocytosis as a main mechanism of the transfer. We argue that once the micelle or vesicle comes to the surface of the membrane the energy barriers of both diminish each other and make it equally preferential for the molecule to stay or to move inside the membrane. In that case unfavourable contacts with water molecules will be avoided, whereas drug molecule can get to an energetically more stable environment in the membrane. In that project we aim to investigate the contribution of composition of micelles on the transfer of molecule through the intestinal membrane. 8 molecules (6 drugs: danazol, carbamazepine, felodipine, fenofibrate, acetretin, probucol; surfactant - caprate; and a reference molecule - ethanol), 4 micelle compositions (pure sodium taurocholate, pure phospholipids, mixture NaTC:PL 4:1 and mixture with cholesterol) and 2 membranes (pure POPC and DLiPC with NaTC) will be studied systematically. Umbrella sampling technique will be applied to observe potential of mean force U/kT (R) for pulling the molecule away from the micelle to the bulk, from the bulk to the membrane (and other way around) and from the micelle straight to the membrane. We expect the data to prove or refute the hypothesis. Further these computational experiments will be repeated in more complex fluids (not solely water), representing simulated intestinal fluids.