The use of quantum mechanical potentials in protein-ligand affinity prediction is becoming increasingly feasible with growing computational power. To move forward, validation of such potentials on real-world challenges is necessary. To this end, we have collated an extensive set of over a thousand galectin inhibitors with known affinities and docked them into galectin-3. The docked poses were then used to systematically evaluate several modern force fields and semiempirical quantum mechanical (SQM) methods up to the tight-binding level under consistent computational workflow. Implicit solvation models available with the tested methods were used to simulate solvation effects. Overall, the best methods in this study achieved a Pearson correlation of 0.7-0.8 between the computed and experimental affinities. There were differences between the tested methods in their ability to rank ligands across the entire ligand set as well as within subsets of structurally similar ligands. A major discrepancy was observed for a subset of ligands that bind to the protein via a halogen bond, which was clearly challenging for all the tested methods. The inclusion of an entropic term calculated by the rigid-rotor-harmonic-oscillator approximation at SQM level slightly worsened correlation with experiment but brought the calculated affinities closer to experimental values. We also found that the success of the prediction strongly depended on the solvation model. Furthermore, we provide an in-depth analysis of the individual energy terms and their effect on the overall prediction accuracy.

• MeSH
• Galectins * metabolism   chemistry   antagonists & inhibitors   MeSH
• Quantum Theory * MeSH
• Ligands MeSH
• Molecular Docking Simulation MeSH
• Protein Binding MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Galectins * MeSH
• Ligands MeSH

Carborane-based compounds are promising lead structures for development of inhibitors of carbonic anhydrases (CAs). Here, we report structural and computational analysis applicable to structure-based design of carborane compounds with selectivity toward the cancer-specific CAIX isoenzyme. We determined the crystal structure of CAII in complex with 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane at 1.0 Å resolution and used this structure to model the 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane interactions with CAIX. A virtual glycine scan revealed the contributions of individual residues to the energy of binding of 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane to CAII and CAIX, respectively.

• MeSH
• Glycine chemistry   MeSH
• Carbonic Anhydrase Inhibitors chemistry   pharmacology   MeSH
• Carbonic Anhydrases chemistry   MeSH
• Catalytic Domain MeSH
• Crystallography, X-Ray MeSH
• Quantum Theory * MeSH
• Humans MeSH
• Models, Molecular * MeSH
• Boron Compounds chemistry   pharmacology   MeSH
• Substrate Specificity drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• dodecaborate MeSH Browser
• Glycine MeSH
• Carbonic Anhydrase Inhibitors MeSH
• Carbonic Anhydrases MeSH
• Boron Compounds MeSH