Connecting Drug Discovery with Solid State Formulation Design
Lead Research Organisation:
University of Leeds
Department Name: Chemical and Process Engineering
Abstract
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.
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.
Planned Impact
The CDT in Molecules to Product has the potential to make a real impact as a consequence of the transformative nature of the underpinning 'design and supply' paradigm. Through the exploitation of the generated scientific knowledge, a new approach to the product development lifecycle will be developed. This know-how will impact significantly on productivity, consistency and performance within the speciality chemicals, home and personal care (HPC), fast moving consumer goods (FMCG), food and beverage, and pharma/biopharma sectors.
UK manufacturing is facing a major challenge from competitor countries such as China that are not constrained by fixed manufacturing assets, consequently they can make products more efficiently and at significantly lower operational costs. For example, the biggest competition for some well recognised 'high-end' brands is from 'own-brand' products (simple formulations that are significantly cheaper). For UK companies to compete in the global market, there is a real need to differentiate themselves from the low-cost competition, hence the need for uncopiable or IP protected, enhanced product performance, higher productivity and greater consistency. The CDT is well placed to contribute to addressing this shift in focus though its research activities, with the PGR students serving as ambassadors for this change. The CDT will thus contribute to the sustainability of UK manufacturing and economic prosperity.
The route to ensuring industry will benefit from the 'paradigm' is through the PGR students who will be highly employable as a result of their unique skills-set. This is a result of the CDT research and training programme addressing a major gap identified by industry during the co-creation of the CDT. Resulting absorptive capacity is thus significant. In addition to their core skills, the PGR students will learn new ones enabling them to work across disciplinary boundaries with a detailed understanding of the chemicals-continuum. Importantly, they will also be trained in innovation and enterprise enabling them to challenge the current status quo of 'development and manufacture' and become future leaders.
The outputs of the research projects will be collated into a structured database. This will significantly increase the impact and reach of the research, as well as ensuring the CDT outputs have a long-term transformative effect. Through this route, the industrial partners will benefit from the knowledge generated from across the totality of the product development lifecycle. The database will additionally provide the foundations from which 'benchmark processes' are tackled demonstrating the benefits of the new approach to transitioning from molecules to product.
The impact of the CDT training will be significantly wider than the CDT itself. By offering modules as Continuing Professional Development courses to industry, current employees in chemical-related sectors will have the opportunity to up-skill in new and emerging areas. The modules will also be made available to other CDTs, will serve as part of company graduate programmes and contribute to further learning opportunities for those seeking professional accreditation as Chartered Chemical Engineers.
The CDT, through public engagement activities, will serve as a platform to raise awareness of the scientific and technical challenges that underpin many of the items they rely on in daily life. For example, fast moving consumer goods including laundry products, toiletries, greener herbicides, over-the-counter drugs and processed foods. Activities will include public debates and local and national STEM events. All events will have two-way engagement to encourage the general public to think what the research could mean for them. Additionally these activities will provide the opportunity to dispel the myths around STEM in terms of career opportunities and to promote it as an activity to be embraced by all thereby contributing to the ED&I agenda.
UK manufacturing is facing a major challenge from competitor countries such as China that are not constrained by fixed manufacturing assets, consequently they can make products more efficiently and at significantly lower operational costs. For example, the biggest competition for some well recognised 'high-end' brands is from 'own-brand' products (simple formulations that are significantly cheaper). For UK companies to compete in the global market, there is a real need to differentiate themselves from the low-cost competition, hence the need for uncopiable or IP protected, enhanced product performance, higher productivity and greater consistency. The CDT is well placed to contribute to addressing this shift in focus though its research activities, with the PGR students serving as ambassadors for this change. The CDT will thus contribute to the sustainability of UK manufacturing and economic prosperity.
The route to ensuring industry will benefit from the 'paradigm' is through the PGR students who will be highly employable as a result of their unique skills-set. This is a result of the CDT research and training programme addressing a major gap identified by industry during the co-creation of the CDT. Resulting absorptive capacity is thus significant. In addition to their core skills, the PGR students will learn new ones enabling them to work across disciplinary boundaries with a detailed understanding of the chemicals-continuum. Importantly, they will also be trained in innovation and enterprise enabling them to challenge the current status quo of 'development and manufacture' and become future leaders.
The outputs of the research projects will be collated into a structured database. This will significantly increase the impact and reach of the research, as well as ensuring the CDT outputs have a long-term transformative effect. Through this route, the industrial partners will benefit from the knowledge generated from across the totality of the product development lifecycle. The database will additionally provide the foundations from which 'benchmark processes' are tackled demonstrating the benefits of the new approach to transitioning from molecules to product.
The impact of the CDT training will be significantly wider than the CDT itself. By offering modules as Continuing Professional Development courses to industry, current employees in chemical-related sectors will have the opportunity to up-skill in new and emerging areas. The modules will also be made available to other CDTs, will serve as part of company graduate programmes and contribute to further learning opportunities for those seeking professional accreditation as Chartered Chemical Engineers.
The CDT, through public engagement activities, will serve as a platform to raise awareness of the scientific and technical challenges that underpin many of the items they rely on in daily life. For example, fast moving consumer goods including laundry products, toiletries, greener herbicides, over-the-counter drugs and processed foods. Activities will include public debates and local and national STEM events. All events will have two-way engagement to encourage the general public to think what the research could mean for them. Additionally these activities will provide the opportunity to dispel the myths around STEM in terms of career opportunities and to promote it as an activity to be embraced by all thereby contributing to the ED&I agenda.
