HPC-Europa 3 visit: molecular modelling of galectin binding compounds

Author: Guest blogger
Posted: 12 Apr 2018 | 12:22

Dr Domenica Capasso was our first HPC-Europa3 visitor at EPCC but was hosted remotely at UCL from Nov 2017 to Dec 2017. She relates her experiences and research in this blog article.

I recently spent a month in London funded by the HPC-Europa3 programme and hosted by Prof. Francesco Luigi Gervasio at the Department of Chemistry at UCL. This was an exciting experience for me, primarily for my research work but it also provided me with an opportunity to visit London, a city I had never been to before. I arrived in London with interesting biological results on some potential inhibitors of the galectins class of proteins, which had been synthesized at my Institute in Naples. Galectins (Gal) are β-D-galactoside binding proteins that have important implications for many diseases including tumourigenesis, inflammatory response and autoimmune disorders. The general aim of this work is to rationally design novel inhibitors of galectins that could be used as anti-cancer and anti-inflammatory therapies.

During my visit, we created a virtual library of candidate compounds targeting galectins using structure-based drug design approaches. To do so, we used information coming from both the crystal structures of Gal-1, -3, and -9 and from alternative conformations of each receptor obtained from molecular dynamics (MD) simulations, using GROMACS v.2016.3, to obtain conformations that could be used in a drug form and exploited to design new inhibitors with higher specificity towards each galectin. Access to HPC resources was crucial for me, as it allowed me to quickly run the necessary MD simulations.

Figure 1. Crystal structure of Gal-3 (cyan) in complex with the galectin inhibitor TD189 (red). The most promising position for scaffold modification are highlighted with arrows.

After we ran a number of simulations, we used Schrödinger’s suite to perform virtual screening of the compounds that we designed for each of the crystal structures and the newly identified conformations. The compounds were then ranked according to their resulting binding pose (ie the preferred orientation of a ligand when bound to an enzyme). The most promising compounds obtained from the in-silico study are now being synthesized at the Department of Chemistry of the Federico II University in Naples and they will subsequently be tested on tumour and normal cells to evaluate their activity.

Working with Prof. Gervasio’s group turned out to be very collaborative and interactive, and thus added another positive note to this whole experience. Furthermore, the HPC team at Edinburgh, even though I was not at Edinburgh, constantly supported me, promptly responding to my questions and requests.

All of this happened in the extraordinary city of London. As previously stated, I had never been to London before, and the city just blew me away. It is full of enchanting attractions such as Buckingham Palace, Westminster Abbey, Tower Bridge, and many others. London is a city full of sounds, music stores, fashion, vintage gear, and costume jewellery. The city has an extraordinary fusion of tradition and an avant-garde spirit. Not to mention the parks! Even in the middle of winter, people still go to the parks of London. I hope to come back to visit London in the near future.

HPC-Europa3: http://www.hpc-europa.eu/