Exploring the Conformational Landscape of Bioactive Small Molecules
| Autor: | Sanja Zivanovic, Francesco Colizzi, David Moreno, Adam Hospital, Robert Soliva, Modesto Orozco |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Molecular Conformation Protein Data Bank (RCSB PDB) Química combinatòria Ionic bonding Combinatorial chemistry Ligands 01 natural sciences Force field (chemistry) Small Molecule Libraries Computational chemistry 0103 physical sciences Molecule Teoria quàntica Molècules Physical and Theoretical Chemistry Databases Protein Quantum Density Functional Theory 010304 chemical physics Chemistry Proteins computer.file_format Molecules Protein Data Bank Small molecule Computer Science Applications Molecular Weight Quantum theory computer Macromolecule |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Journal of Chemical Theory and Computation |
| ISSN: | 1549-9626 1549-9618 |
| Popis: | By using a combination of classical Hamiltonian replica exchange with high-level quantum mechanical calculations on more than one hundred drug-like molecules, we explored here the energy cost associated with binding of drug-like molecules to target macromolecules. We found that, in general, the drug-like molecules present bound to proteins in the Protein Data Bank (PDB) can access easily the bioactive conformation and in fact for 73% of the studied molecules the "bioactive" conformation is within 3kBT from the most-stable conformation in solution as determined by DFT/SCRF calculations. Cases with large differences between the most-stable and the bioactive conformations appear in ligands recognized by ionic contacts, or very large structures establishing many favorable interactions with the protein. There are also a few cases where we observed a non-negligible uncertainty related to the experimental structure deposited in PDB. Remarkably, the rough automatic force field used here provides reasonable estimates of the conformational ensemble of drugs in solution. The outlined protocol can be used to better estimate the cost of adopting the bioactive conformation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|