Connecting Drug Discovery with Solid State Formulation Design

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Computer-aided drug design involves making predictions relating to the function and properties of bioactive molecules based on their molecular structure. These models do not take into account the solid-state properties of such molecules, which may control the solubility and bioavailability, two physicochemical properties which can govern the in vivo activity of drugs. The solid form of active pharmaceutical ingredients (APIs), and factors such as salt and hydrate formation, can affect the surface properties and dissolution rate which are critical when considering the bioavailability of solid API formulations. Combining computational approaches used in early stage drug discovery with computational models which can predict solid-state properties, would be a powerful assert to the pharmaceutical and agrochemical industries, with the potential to drastically reduce rates of attrition during development.The aim of the project is to link the structure of a molecule to its solubility properties by generating quantitative structure-property relationship (QSPR) computational models which can predict solid-state properties of ionic bioactive molecules. We postulate that the role of the solid state is not adequately accounted for in the current status-quo models for solubility and bioavailability prediction. To begin we will focus on two chemical structures which are highly relevant to the pharmaceutical industry: quinolin-4-ones and 1,8-naphthyridines. These have been chosen since (i) they are privileged scaffolds, found in a number of clinically relevant drugs; (ii) they form part of active research projects in the Fishwick group at Leeds, where exemplar bioactive molecules display poor solubility in various aqueous systems (<10 uM).To achieve the overall project aim, we have a number of objectives:Objective 1: We aim to develop a new set of descriptors based on various structural features exclusive to the solid state, to help us capture the role of the solid state in bioavailability. This include 'synthonic interactions', the 3D arrangement, stacking and sublimation enthalpies, amongst other features. We believe surface chemistry plays an important role, and the types of surfaces generated from different 3D structures. We wish to use ionic materials which have a propensity to readily form different polymorphs and salt structures to help us quantify the role of these interactions exclusive to the solid state. Objective 2: Train the computational models using experimental data (such as aqueous solubility measurements of different polymorphs and atomic force microscopy), so that these new descriptors may be used in further predictive studies to help improve modelling of properties relevant to bioavailability. Once suitable endpoints have been achieved, the knowledge can feedback into the design-phase of computer-aided drug design.Objective 3: Widen the scope to include additional privileged scaffolds from industrial partners.The project relates to a number of EPSRC research themes: surface science (major alignment), complexity science and control engineering. Our aims will explore many unknowns in surface-based chemistry of ionic substances, connecting experimental data with QSPR modelling.