BioExcel continues its direct support to industry through site visits. In early March we were pleased to participate in an exciting day of collaborative talks hosted by Janssen at their research site in Beerse, Belgium.
The morning comprised of presentations by Janssen’s Computational Chemistry group, led by Herman van Vlijmen who emphasized that now is an exciting time for computational drug design. Principal scientist, Dr Gary Tresadern covered their interests and needs for molecular dynamics (MD) and free energy (FE) calculations applied to molecular design and virtual screening for drug discovery projects. Important challenges are keeping abreast of the latest methodologies and validation of molecular dynamic predictions in a timely manner. Post-doctoral scientist, Dr Laura Perez presented her recent work on free energy perturbations (FEP) applied to the public 3D structure phosphodiesterase 2 (PDE2) published recently: Predicting Binding Free Energies of PDE2 Inhibitors. The Difficulties of Protein Conformation. Pérez-Benito L, Keränen H, van Vlijmen H, Tresadern G. Sci Rep. 2018 Mar 20;8(1):4883. DOI: 10.1038/s41598-018-23039-5. Recent collaboration with BioExcel partner, Dr Vytautas Gapsys on GROMACS (bioexcel.eu/software/Gromacs) and PMX (bioexcel.eu/software/pmx) applied to PDE2 has demonstrated encouraging results.
From: Predicting Binding Free Energies of PDE2 Inhibitors. The Difficulties of Protein Conformation
Figure 2: Conformational states of PDE2 catalytic domain.
After lunch two presentations were given by Janssen’s collaborators. They started with Prof. Leonardo Pardo (UAB, Barcelona) who presented the application of MD to metabotropic glutamate receptor subtypes which possess switches of allosteric modulation: Pérez-Benito L, Doornbos MLJ, Cordomí A, Peeters L, Lavreysen H, Pardo L, Tresadern G. Structure. 2017 Jul 5;25(7):1153-1162.e4. DOI: 10.1016/j.str.2017.05.021. The MD predictions from GROMACS for the trigger switch were validated through making point mutations and showing loss of allosteric modulation in experimental studies. The talk was followed by a presentation by Dr Bart Lenselink (Universiteit Leiden) on the application of MD and FEP to numerous representatives from the G Protein-Coupled Receptor (GPCR) superfamily, making use of Desmond, the MD engine from Schrödinger.
Presentations from the BioExcel partners followed during the remainder of the afternoon. A short introduction to BioExcel was given by Dr Ian Harrow. This was followed by a presentation on the docking tool, HADDOCK (bioexcel.eu/software/haddock) by Prof. Alexandre Bonvin which included top predictions in the blind challenges of D3R (drugdesigndata.org) and CAPRI (ebi.ac.uk/msd-srv/capri). Next, Prof. Erik Lindahl presented on the MD engine GROMACS which included insights into getting best performance. Finally, Dr Vytautas Gapsys presented the PMX alchemical access to GROMACS which included the recent collaboration with Laura and Gary on PDE2, as mentioned above. Throughout the day a number of new opportunities were identified to strengthen the relationships between Janssen Computational Chemistry, collaborators and BioExcel partners.