Exploring the binding mechanism of glycomimetics to galectins through simulations

Author: Guest blogger
Posted: 21 Oct 2019 | 11:13

Domenica Capasso was an HPC-Europa visitor to University College London from 12 June to 11 August 2019. In this blog article she describes her work and time in London.

In June this year, I returned to London and I spent two months at the Department of Chemistry at UCL, funded by HPC-Europa and hosted by Professor Francesco Luigi Gervasio. My project concerns the galectins, β-D-galactoside binding proteins with important implications for tumorigenesis, inflammatory response and autoimmune disorders. During my first visit, we created a virtual library of candidate compounds, containing two saccharide residues with a bridging sulphur/selenium atom. These derivatives, targeting galectins, were obtained using structure-based drug design approaches and are synthesised and tested in my Institute in Naples.

In particular, after extensive binding affinity experiments, we demonstrated that some derivatives improve the binding affinity with respect to the lead compound. Furthermore, we revealed that the bridging atom is very important for the binding: mono-sulphide and mono-selenide digalactoside derivatives are able to bind galectin-3, while di-sulphide or di-selenide digalactoside derivatives show very low or no binding affinity respectively against Gal-3. Therefore, during this second visit, we rationalised the difference in the affinity of the mono-sulphide/selenide digalactoside derivatives against Gal-3 over the disulphide/diselenide ones using a combination of computational techniques that allowed us to study the binding mode of the diglycosylated compounds taking into account the flexibility both of the compounds and the Gal-3. For this aim, the access to ARCHER HPC resources was crucial for me, as it allowed me to quickly run the necessary MD simulations.

I was very happy to return to London, firstly to continue working on my project, and then because I would see colleagues from Professor Gervasio’s group, always helpful and interactive. Furthermore, the HPC-Europa team in Edinburgh were really supportive throughout my stay, responding to all my questions.

Finally, I got to know the city of London better. I visited places I hadn’t seen before, even the less tourist ones. From the magnificent and magical Battersea Power Station to the further away Olympic Park. Like the first time, London has once again amazed and fascinated me. I look forward to continuing the project and the collaboration with the Gervasio group. I also hope to have other opportunities to use the HPC facilities and the support of its team.

Figure: Selenodigalactoside (pink sticks) bound to Gal-3. Interacting residues are in blue. The bridging atom is in orange.