As one key step of drug discovery process, the overall profile of a small molecule is optimized in the time course of drug design. Several parameters such as ADME, selectivity towards off-targets and toxicology constitute this profile. We are working on the method development of predictive models that can be used for an artificial intelligence-driven optimization of this profile. Our work is based on previous published studies,(1,2) and it will be extended by improving the computer-readable form of the molecules (aka fingerprints) as well as by improving the interpretability of models.
(1) Czodrowski, P. HERG Me Out. J. Chem. Inf. Model. 2013, 53 (9), 2240-2251.
(2) Czodrowski, P.; Bolick, W.-G. OCEAN: Optimized Cross REActivity EstimatioN. J. Chem. Inf. Model. 2016, 56 (10), 2013-2023.
The comprehensive deciphering of protonation effects upon protein-ligand complexation is one of our long-lasting research interests. We published several cases in which such an effect is observed, experimentally and theoretically. (1–4) In our lab, we will extend this analysis to all available public x-ray structures by means of pKa calculations. Furthermore, we are planning to measure small molecule pKa values via potentiometric methods. These pKa values are crucial as starting point for the protein-ligand pKa calculations. We will also establish ITC measurements in order to experimentally prove the predicted protonation changes.(2) This high-quality data will be then used for the method development of protein-ligand pKa calculations.
(1) Schauperl, M.; Czodrowski, P.; Fuchs, J. E.; Huber, R. G.; Waldner, B. J.; Podewitz, M.; Kramer, C.; Liedl, K. R. Binding Pose Flip Explained via Enthalpic and Entropic Contributions. J. Chem. Inf. Model. 2017, 57 (2), 345–354.
(2) Neeb, M.; Czodrowski, P.; Heine, A.; Barandun, L. J.; Hohn, C.; Diederich, F.; Klebe, G. Chasing Protons: How Isothermal Titration Calorimetry, Mutagenesis, and PKa Calculations Trace the Locus of Charge in Ligand Binding to a TRNA-Binding Enzyme. J. Med. Chem. 2014, 57 (13).
(3) Czodrowski, P. Who Cares for the Protons? Bioorg. Med. Chem. 2012, 20 (18), 5453–5460.
(4) Czodrowski, P.; Sotriffer, C. A.; Klebe, G. Protonation Changes upon Ligand Binding to Trypsin and Thrombin: Structural Interpretation Based on PK(a) Calculations and ITC Experiments. J. Mol. Biol. 2007, 367 (5), 1347–1356.