<> "The repository administrator has not yet configured an RDF license."^^ . <> . . . "Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments"^^ . "Rational drug design focuses on the explanation and prediction of\r\ncomplex formation between therapeutic targets and small-molecule ligands. As a\r\nthird and often overlooked interacting partner, water molecules play a critical role\r\nin the thermodynamics of protein−ligand binding, impacting both the entropy and\r\nenthalpy components of the binding free energy and by extension, on-target affinity\r\nand bioactivity. The community has realized the importance of binding site waters,\r\nas evidenced by the number of computational tools to predict the structure and\r\nthermodynamics of their networks. However, quantitative experimental characterization of relevant protein−ligand−water systems, and consequently the validation of these modeling methods, remains challenging.\r\nHere, we investigated the impact of solvent exchange from light (H2O) to heavy water (D2O) to provide complete thermodynamic\r\nprofiling of these ternary systems. Utilizing the solvent isotope effects, we gain a deeper understanding of the energetic contributions\r\nof various components. Specifically, we conducted isothermal titration calorimetry experiments on trypsin with a series of psubstituted benzamidines, as well as carbonic anhydrase II (CAII) with a series of aromatic sulfonamides. Significant differences in\r\nbinding enthalpies found between light vs heavy water indicate a substantial role of the binding site water network in protein−ligand\r\nbinding. Next, we challenged two conceptually distinct modeling methods, the grid-based WaterFLAP and the molecular dynamicsbased MobyWat, by predicting and scoring relevant water networks. The predicted water positions accurately reproduce those in\r\navailable high-resolution X-ray and neutron diffraction structures of the relevant protein−ligand complexes. Estimated energetic\r\ncontributions of the identified water networks were corroborated by the experimental thermodynamics data. Besides providing a\r\ndirect validation for the predictive power of these methods, our findings confirmed the importance of considering binding site water\r\nnetworks in computational ligand design."^^ . "2024" . . "64" . "23" . . "JOURNAL OF CHEMICAL INFORMATION AND MODELING"^^ . . . "15499596" . . . . . . . . . . . . . . . . . . . . . . . . . . . . "Janez"^^ . "Ilaš"^^ . "Janez Ilaš"^^ . . "Rita"^^ . "Börzsei"^^ . "Rita Börzsei"^^ . . "Dávid"^^ . "Bajusz"^^ . "Dávid Bajusz"^^ . . "Balázs Zoltán"^^ . "Zsidó"^^ . "Balázs Zoltán Zsidó"^^ . . "György"^^ . "Ferenczy"^^ . "György Ferenczy"^^ . . "György Miklós"^^ . "Keserű"^^ . "György Miklós Keserű"^^ . . "Csaba"^^ . "Hetényi"^^ . "Csaba Hetényi"^^ . . "Tibor Viktor"^^ . "Szalai"^^ . "Tibor Viktor Szalai"^^ . . "Gyógyszerkémiai Kutatócsoport HRN TTK / SZKI GyKKCs [2014-]"^^ . . . "Farmakológiai és Farmakoterápiai Intézet PTE / ÁOK FFI"^^ . . . "Szerves Kémia és Technológia Tanszék BME / VBK SZKTT [2006-]"^^ . . . . . . . "Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Text)"^^ . . . . . . "szalai2024.pdf"^^ . . . "Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)"^^ . . . . . . "small.jpg"^^ . . . "Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #223201 \n\nEffect of Water Networks On Ligand Binding: Computational Predictions vs Experiments\n\n" . "text/html" . . . "QD Chemistry / kémia"@en . .