Comprehensive Assessment of Torsional Strain in Crystal Structures of Small Molecules and Protein-Ligand Complexes using ab Initio Calculations
| Autor: | Brajesh K. Rai, Meihua Tu, Raymond J. Unwalla, Vishnu Sresht, Gregory A. Bakken, Alan M. Mathiowetz, Qingyi Yang |
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| Rok vydání: | 2019 |
| Předmět: |
Steric effects
Materials science Rotation General Chemical Engineering Protein Data Bank (RCSB PDB) Molecular Conformation Library and Information Sciences Ligands 01 natural sciences Small Molecule Libraries Ab initio quantum chemistry methods 0103 physical sciences Drug Discovery Molecule Conformational isomerism 010304 chemical physics Strain (chemistry) Molecular Structure Proteins Hydrogen Bonding General Chemistry computer.file_format Protein Data Bank 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry Crystallography computer Databases Chemical Protein ligand |
| Zdroj: | Journal of chemical information and modeling. 59(10) |
| ISSN: | 1549-960X |
| Popis: | The energetics of rotation around single bonds (torsions) is a key determinant of the three-dimensional shape that druglike molecules adopt in solution, the solid state, and in different biological environments, which in turn defines their unique physical and pharmacological properties. Therefore, accurate characterization of torsion angle preference and energetics is essential for the success of computational drug discovery and design. Here, we analyze torsional strain in crystal structures of druglike molecules in Cambridge structure database (CSD) and bioactive ligand conformations in protein data bank (PDB), expressing the total strain energy as a sum of strain energy from constituent rotatable bonds. We utilized cloud computing to generate torsion scan profiles of a very large collection of chemically diverse neutral fragments at DFT(B3LYP)/6-31G*//6-31G** or DFT(B3LYP)/6-31+G*//6-31+G** (for sulfur-containing molecule). With the data generated from these ab initio calculations, we performed rigorous analysis of strain due to deviation of observed torsion angles relative to their ideal gas-phase geometries. Contrary to the previous studies based on molecular mechanics, we find that in the crystalline state, molecules generally adopt low-strain conformations, with median per-torsion strain energy in CSD and PDB under one-tenth and one-third of a kcal/mol, respectively. However, for a small fraction ( |
| Databáze: | OpenAIRE |
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