Conformational free energy modeling of druglike molecules by metadynamics in the WHIM space

Journal of Chemical Information and Modeling
Vojtech SpiwokBlanka Králová

Abstract

Protein-ligand affinities can be significantly influenced not only by the interaction itself but also by conformational equilibrium of both binding partners, free ligand and free protein. Identification of important conformational families of a ligand and prediction of their thermodynamics is important for efficient ligand design. Here we report conformational free energy modeling of nine small-molecule drugs in explicitly modeled water by metadynamics with a bias potential applied in the space of weighted holistic invariant molecular (WHIM) descriptors. Application of metadynamics enhances conformational sampling compared to unbiased molecular dynamics simulation and allows to predict relative free energies of key conformations. Selected free energy minima and one example of transition state were tested by a series of unbiased molecular dynamics simulation. Comparison of free energy surfaces of free and target-bound Imatinib provides an estimate of free energy penalty of conformational change induced by its binding to the target.

References

Jun 1, 1995·Protein Science : a Publication of the Protein Society·J N VargheseP M Colman
Jul 1, 1995·Protein Science : a Publication of the Protein Society·A J Doig, R L Baldwin
Dec 1, 1993·Proteins·A AmadeiH J Berendsen
Oct 20, 1998·Journal of Computer-aided Molecular Design·J BoströmT Liljefors
Feb 5, 1999·Journal of Molecular Biology·D W Miller, D A Agard
May 12, 2001·Science·E S Istvan, J Deisenhofer
Sep 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Alessandro Laio, Michele Parrinello
Apr 27, 2004·Nature Structural & Molecular Biology·Steve TuskeEddy Arnold
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jul 24, 2004·Acta Crystallographica. Section D, Biological Crystallography·Alexander W Schüttelkopf, Daan M F van Aalten
Jun 21, 2006·Proceedings of the National Academy of Sciences of the United States of America·Payel DasCecilia Clementi
Jul 21, 2006·The Journal of Physical Chemistry. B·Alessandro LaioMichele Parrinello
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Jun 12, 2009·Current Medicinal Chemistry·Nicolas Foloppe, I-Jen Chen
Jun 12, 2009·Human Molecular Genetics·Aurélie DipietromariaReiner A Veitia
Sep 28, 2010·Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics·Yanier CrespoAlessandro Laio
Apr 19, 2011·Journal of Computational Chemistry·Jens Smiatek, Andreas Heuer
Aug 23, 2011·The Journal of Physical Chemistry. B·Andrea PavlouEftychia Pinakoulaki
Mar 1, 2008·Journal of Chemical Theory and Computation·Berk HessErik Lindahl

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Citations

Dec 9, 2014·Biotechnology Advances·Vojtech SpiwokPetr Hosek
Jan 16, 2014·Organic & Biomolecular Chemistry·Andrea SartoriFranca Zanardi

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