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00925njm 22002777a 4500 dc Zivanovic, Sanja author Colizzi, Francesco author Moreno Fajardo, David Fernando author Hospital Gasch, Adam author Soliva, Robert author Orozco López, Modesto author 2021-07-19T06:46:02Z 2021-08-10T05:10:23Z 2020-07-10 2021-07-15T11:27:58Z 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 bioactiveconformation 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. Teoria quàntica Molècules Química combinatòria Quantum theory Molecules Combinatorial chemistry Exploring the Conformational Landscape of Bioactive Small Molecules