Prediction of protein-ligand binding affinities using 3D machine learning methods

3D machine learning methods offer the potential to bridge the gap between docking and FEP, providing high throughput predictions of protein-ligand binding affinities with higher accuracy than classical docking scoring functions. Atomic environment vectors (AEVs) have been shown to be a promising representation for both rapid calculation of quantum mechanical conformational energies of small molecules, and in predicting protein-ligand binding affinities. In the 2022 rotation project, we applied these methods to predict the energy of of non-covalent interactions, in particular hydrogen bonds. Future directions include sharing parameters between elements, including charge and hybridization state as features, and transfer learning from the non-covalent interaction task to the protein-ligand binding task. It is also of interest to explore how AEVs can be used in molecular dynamics simulations following upon recent results from Roitberg on simulating a protein-ligand complex using ANI. These methods could be useful for including the entropic contributions to binding affinities as well as the enthalpic contributions from non-covalent interactions. This project would aim to test models on binding affinity and test the extent to which these models robustly learn non-covalent interactions and have improved generalizability over the prevailing ligand-based models for predicting binding affinity. This project falls into the EPSRC Biological informatics research area due to the use of computational modeling of biological systems using chemical and biological data. GSK is a collaborating company.

The main impact of the SABS CDT will be the difference made by the scientists trained within it, both during their DPhils and throughout their future careers.

The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.

Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners

"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."

New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.

For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,

"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."

However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.

The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students

"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."

To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.

The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.