Binding free energy and ligand orientation calculations using a Monte Carlo method with Markov Sate analysis
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Tipus de documentText en actes de congrés
Data publicació2015-05-05
EditorBarcelona Supercomputing Center
Condicions d'accésAccés obert
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Reconeixement-NoComercial-SenseObraDerivada 3.0 Espanya
Abstract
Computing binding free energies has great
implications in drug design. Using PELE technique, it has been
shown that one can get quick and accurate estimations by means of a
Markov state model3. We improved our methodology to compute
faster binding relative free energy differences, mainly by analysis
reducing the sampled region. This possibility opens a way in all-atom
drug lead optimization by efficiently scoring a list of potential
candidates in terms of binding affinities (approximately in 24hours),
while still modeling accurately the protein-drug induced fit.
Furthermore, we added information of the ligand orientation
allowing us to obtain a better insight of the entrance mechanism.
First, we show benchmark results - a series of benzamidine-like
inhibitors in trypsin. Then, we apply our method to a more realistic
scenario: the binding to a glucocorticoid receptor, and we show the
performance for a new benchmark with a larger range of binding free
energies (~14 kcal/mol). Simulations are obtained with our new
in-house code PELE++, an improvement over the technique
presented in references [1,2], (paper in preparation).
CitacióLecina-Casas, Daniel; Takahashi, Ryoji; Guallar, Victor. Binding free energy and ligand orientation calculations using a Monte Carlo method with Markov Sate analysis. A: "BSC Doctoral Symposium (2nd: 2015: Barcelona)". 2nd ed. Barcelona: Barcelona Supercomputing Center, 2015, p. 123-124.
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