Speaker
Description
Computational treatment of ligand:protein interactions represents an old, but yet unsolved challenge in theoretical chemistry. It has been shown by us and others that quantum chemical methods are a preferred option in (semi)quantitative description of ligand binding. Sometimes denoted as “QM/MM-scoring”, the hybrid quantum mechanical and molecular mechanical (QM/MM) approach, combined with X-ray crystallography, molecular docking and conformational sampling, seems to be the most promising approach for the computational ligand (drug) design. The accuracy of the QM/MM approaches, though, comes at a price of huge computational resources requested by the calculations which are available in supercomputer centres.
Specifically, within the IT4I project(s), we focused on the stimulator of interferon genes (STING), a protein that is central to the immune system and whose activation and inhibition represents an underexplored therapeutic target in medicinal chemistry.
The natural ligand of the STING is the cyclic dinucleotide 2′,3′-cGAMP (cyclic [G(2′,5′)pA(3′,5′)p]), which is synthetized by the cyclic- GMP-AMP synthase, upon detection of the double-stranded DNA in the cytosol.
Exploring state-of-the-art methods of computational chemistry, we evaluated interactions of various modified cyclic dinucleotides with the STING, always linking the computed data to experiments. The collaborative efforts of the STING project team led to several patents, collaboration with a small start-up company that would attempt to drive them to clinical tests and computer design of novel ligands.
