Molecular Simulation of oil-water partition coefficients of pharma compounds

The pharmaceutical industry spends a large amount of time and effort (Herper, 2017) in developing potential drug candidates, most of which are eventually discarded due to lack of solubility, toxicity, pharmacodynamics issues amongst a range of other hurdles.
Through costly experimentation, many candidate drugs are found to be a 'dead-end' in spite the time and effort put into their development. Therefore, it would be beneficial to develop in silico alternatives to find potential drug candidates as this would significantly streamline the overall discovery process. Over the years there has been a vast development in the field of molecular modelling, where useful information is obtained at the atomistic level. Many of these methods, however, only provide a snapshot of molecular behaviour.
An alternative methodology, which is computationally faster that the standard atomistic methods, is coarse graining (Ingólfsson, et al., 2014). In this method rather than having explicit atomistic detail there is a representation of different groups of atoms in the form of beads. Larger structures can be modelled using CG methods. This method allows the exploration of phase space currently unexplored and is an exciting area to gain insight in.
This PhD project aims to develop a protocol to evaluate oil-water partition coefficients of active pharmaceutical compounds (APIs). This is an important investigation as the octanol-water partition model is still the foundation of obtaining an initial understanding of the solubility of APIs. The equilibrium concentration of a compound in each phase helps determine how lipophilic or hydrophilic a compound is (Bannan, et al., 2016). The water represents the aqueous media in the human body and the octanol represents biological membranes. Hence, the model is a surrogate for deciding the solubility of API in the body, and their transport across biological membranes. However, currently this is modelled through costly lab experiments.
This project aims to create a suitable computational model to represent this experiment. A coarse-grained model will be used in which an API molecule is 'pulled' by an external force through the water-oil interface. During this process the energy barriers will be monitored to gain a deeper understanding of the transport process. Monitoring the energy barriers will also allow trends and relationships to be determined, if any. This should also help assess the current model used and determine why it may fail to fully represent the actual process of a drug distributing in the body. One of the main limitations of the experimental model is that it fails to account for non-equilibrium conditions. The computational model created should help gain insight into this part of the process.
A large part of this project will involve the development of a suitable and accurate models. Therefore, the first stages of the project will involve doing an extensive literature review of the current models being used, such as atomistic models. A comparison will need to be made between these models, which will help inform the use of a coarse graining model in this project. There will also be other key milestones before the model can be fully set-up and simulated. These have been split into categories in the objectives, seen in the next section