Xxxxxxx Pharmaceutica NV. Xxxxxxx’x interests are in developing and using advanced molecular simulation methods to optimize lead compounds in discovery programs. Such methods, if proven robust and accurate could have a profound impact on the way drug discovery is performed. They would permit reliable computational triaging of very close analogue molecules greatly improving efficiency. Also, this would lead to high-confidence design of synthetically more challenging molecules leading to better drugs in new chemical space. Also, we envisage the accurate prediction of compound binding for targets that have mutated residues. This latter application can be of value in diagnostics, by predicting the best possible compound for a patient clinically (personalised medicine), but is also of use in discovery, where mutated targets occur regularly in antibacterials, antivirals, and oncology compounds. Xxxxxxx has been actively collaborating with UCL on calculation of free energies of binding on public and on Xxxxxxx internal compound sets (targets BRD4, LDHA and PDE2). A manuscript has been co-written and just accepted for publication on the BRD4 application. A second manuscript is under preparation describing the LDHA application. Both cases have led to learnings about the suitable application of MMPBSA, so called ESMACS approach, for the calculation of binding free energies. A third large and extensive study has been mostly completed and in the early stages of write up for publication. This study has involved the use of alchemical perturbation methods, the TIES approach was performed at the UCL group, and the FEP+ approach at Xxxxxxx. Results have been performed for multiple perturbations from various different protein targets. A particular focus has been to investigate the precision of both methods when submitted to extensive repeated trial calculations. The TIES work has also required new replica exchange methodology recently implemented for TIES in the Xxxxxxx group [21, 22, 23]. Within Xxxxxxx, they evaluated the use of GROMACS for Free Energy Perturbation. They streamlined the application of FEP with GROMACS with the help of HPC experts at SURFsara and ran calculations on the Cartesius system also at SURFsara. Calculations were performed and compared with Xxxxxxxxxxx’s FEP+ software. We studied multiple datasets, generating lots of valuable insights on the strengths and limitations of GROMACS FEP. Parts of this work were included in our recent publication [24]. Xxxxxxx completed a study ...
