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The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger FEP

Yuan Hu, Brad Sherborne, Tai-Sung Lee, David A. Case, Darrin M. York, Zhuyan Guo
2016 Journal of Computer-Aided Molecular Design  
Finally, promising results comparing AMBER TI and Schrödinger FEP? are shown that should encourage others to explore the value of TI in routine Structure-based Drug Design.  ...  Keywords Protonation Á Tautomerization Á Free energy calculation Á Thermodynamic integration Á Free energy perturbation Á Protein-ligand binding affinity Abbreviations TI Thermodynamic integration FEP  ...  We thank the AMBER FEW developers Nadine Homeyer and Holger Gohlke for valuable help and discussions in building the workflows. We thank the High Performance Computing (HPC) support at Merck.  ... 
doi:10.1007/s10822-016-9920-5 pmid:27480697 fatcat:7glqycrgl5a5fjqmpecdjeyutq

Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool

Johannes Karwounopoulos, Marcus Wieder, Stefan Boresch
2022 Frontiers in Molecular Biosciences  
We present the software package transformato for the setup of large-scale relative binding free energy calculations.  ...  For selected cases, we checked that the relative binding free energy differences between pairs of ligands do not depend on the choice of the intermediate common core structure.  ...  We thank Åsmund Kaupang for many helpful discussions and the careful reading of the manuscript.  ... 
doi:10.3389/fmolb.2022.954638 pmid:36148009 pmcid:PMC9485484 fatcat:5k7wjuf4yvgbbhvspaoo4x35hi

Assessing the accuracy of octanol-water partition coefficient predictions in the SAMPL6 Part II log P Challenge [article]

Mehtap Işık, Teresa Danielle Bergazin, Thomas Fox, Andrea Rizzi, John D. Chodera, David L. Mobley
2020 bioRxiv   pre-print
There was a 50% increase in the number of participating groups and a 20% increase in the number of submissions compared to the SAMPL5 log D Challenge.  ...  The SAMPL Challenges aim to focus the biomolecular and physical modeling community on issues that limit the accuracy of predictive modeling of protein-ligand binding for rational drug design.  ...  From our comparison of our reference calculations and those with the InterX and MD-AMBER, we find that the choice of 684 input tautomer has a significant effect on log P predictions.  ... 
doi:10.1101/2020.01.20.913178 fatcat:wy46jpugp5fv5ljoqrj3m7yzbu

Computational Prediction of Metabolism: Sites, Products, SAR, P450 Enzyme Dynamics, and Mechanisms

Johannes Kirchmair, Mark J. Williamson, Jonathan D. Tyzack, Lu Tan, Peter J. Bond, Andreas Bender, Robert C. Glen
2012 Journal of Chemical Information and Modeling  
and modeling approaches is accelerating the development of effective tools for prediction of in vivo metabolism, which is reflected by the diverse and comprehensive data sources and methods for metabolism  ...  This review provides a broad overview of structure- and ligand-based computational methods for the prediction of xenobiotic metabolism.  ...  The approach was tested on a set of 12 known binders of CYP2C9, and the RMSD for predicted binding affinity was 2.9 kJ/mol.  ... 
doi:10.1021/ci200542m pmid:22339582 pmcid:PMC3317594 fatcat:z3rgdgqxrrgupcyvshb6kqurbe

Best practices for constructing, preparing, and evaluating protein-ligand binding affinity benchmarks [article]

David F. Hahn, Christopher I. Bayly, Hannah E. Bruce Macdonald, John D. Chodera, Vytautas Gapsys, Antonia S. J. S. Mey, David L. Mobley, Laura Perez Benito, Christina E.M. Schindler, Gary Tresadern, Gregory L. Warren
2021 arXiv   pre-print
(3) analysis of the resulting predictions to enable statistically meaningful comparisons among methods and force fields.  ...  expected when these methods are applied within their domain of applicability, and developers with a way to assess the expected impact of new methodologies.  ...  the performance of Amber/TI calculations [23] , Flare's FEP (a collaboration between Cresset and the Michel group) [24] , and PMX/Gromacs [25] , as well as machine learning studies [26, 27] .  ... 
arXiv:2105.06222v2 fatcat:s2wagrcp3rcftnpk4loryagsmq

Best Practices for Alchemical Free Energy Calculations [article]

Antonia S. J. S. Mey, Bryce Allen, Hannah E. Bruce Macdonald, John D. Chodera, Maximilian Kuhn, Julien Michel, David L. Mobley, Levi N. Naden, Samarjeet Prasad, Andrea Rizzi, Jenke Scheen, Michael R. Shirts (+2 others)
2020 arXiv   pre-print
In this paper, we review current best practices for several popular application domains of alchemical free energy calculations, including relative and absolute small molecule binding free energy calculations  ...  Alchemical free energy calculations are a useful tool for predicting free energy differences associated with the transfer of molecules from one environment to another.  ...  This type of scheme is currently used for AMBER TI calculations [17] and for Sire as implemented in BioSimSpace [34] .  ... 
arXiv:2008.03067v3 fatcat:u7subh2ndzamtg5ewjllg2y2fm

Structure-based virtual screening: an overview

Paul D Lyne
2002 Drug Discovery Today  
Here, the current strengths and weaknesses of the technology are discussed, and emphasis is placed on aspects of the work-flow of a virtual screening campaign, from preparation through to post-screening  ...  Enormous advances in genomics have resulted in a large increase in the number of potential therapeutic targets that are available for investigation.  ...  Empirical-based methods rely on the availability of protein-ligand complexes with known binding affinity, and consequently they have been derived based on a relatively small set (~100) of publicly available  ... 
doi:10.1016/s1359-6446(02)02483-2 pmid:12546894 fatcat:euk2uk3dfjbxleqe4nz6c77n4i

Best Practices for Alchemical Free Energy Calculations [Article v1.0]

Antonia S.J.S Mey, Bryce K. Allen, Hannah E. Bruce Macdonald, John D. Chodera, David F. Hahn, Maximilian Kuhn, Julien Michel, David L. Mobley, Levi N. Naden, Samarjeet Prasad, Andrea Rizzi, Jenke Scheen (+3 others)
2019 Living journal of computational molecular science  
This type of scheme is currently used for AMBER TI calculations [17] and for Sire as implemented in BioSimSpace [34] .  ...  That is, assume that the standard deviation in the relative binding free energies for the changes represented is RT ln 5 (corresponding to a 5-fold change in the binding affinities), and that 1 in 10 new  ... 
doi:10.33011/2.1.18378 fatcat:g3fda3stxrchhmahqrbwci6ena

An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications

Maral Aminpour, Carlo Montemagno, Jack A. Tuszynski
2019 Molecules  
The first example describes in silico modeling of the adsorption of small molecules to organic and inorganic surfaces, which may be applied to drug delivery issues.  ...  In this paper we review the current status of high-performance computing applications in the general area of drug discovery.  ...  Acknowledgments: To the memory of Carlo Montemagno, my advisor, my mentor and a great human being.  ... 
doi:10.3390/molecules24091693 fatcat:jcrxkk3uwrctlcvg6jkkqolqia

Using Theoretical Chemistry to understand the Properties of Polyoxometalates and their potential as energy storage materials

EMANUELE FALBO
2022 figshare.com  
Besides the understanding of the role of the proton, the use of free energy sampling techniques, like TI and FNE, alongside AIMD simulations, can give a quantitative description of the electron (proton  ...  This illustrates the importance of explicit description of the solvation shell in predicting the redox properties of POMs.  ...  The main challenge is indeed represented by exactly determining the correspondence between the number of electrons and protons taking part in the reaction and their relative redox potentials.  ... 
doi:10.6084/m9.figshare.19701547.v1 fatcat:dyy7r5htwrgn5jlievfvieorry

FREE ENERGY SIMULATIONS AND STRUCTURAL STUDIES OF PROTEIN-LIGAND BINDING AND ALLOSTERY [article]

(:Unkn) Unknown, University, My, Ronald M. Levy, Vincent Voelz
2020
Protein-ligand binding and protein allostery play a crucial role in cell signaling, cell regulation, and modern drug discovery.  ...  disease-related proteins and developed a novel alchemical-based free energy method, restrain free energy release (R-FEP-R) to overcome the difficulties in choosing appropriate collective variables and  ...  We gratefully acknowledge Anthony Cruz-Balberdy, Steven Ramsey, and Jason Swails for providing helpful discussions. M. K. G. is a cofounder and has equity interest in the company VeraChem LLC.  ... 
doi:10.34944/dspace/1390 fatcat:smjq5bgjrjdyhf3qfyvg73zsqu

The Development and Assessment of Computational Approaches to the Thermodynamics and Kinetics of Binding

I Lukac
2017
The protonation and tautomeric states of Asp, Glu, Arg, Lys and His were adjusted to match a pH of 7.4. All water molecules and cofactors were removed.  ...  The remainder of the protein is deleted. Tautomeric and protonation states of the protein must be assigned. 3) Theand Cβ atoms are identified.  ... 
doi:10.24377/ljmu.t.00005502 fatcat:slhglpv4mrfwhglh7lz5rkkpom

Mixed-model QSAR at the glucocorticoid and liver X receptors

Angelo Vedani, T. Langer, Morena Spreafico
2009 unpublished
Thanks to Anne and to the other students that spent some time in our lab, for the important professional and personal exchange.  ...  in such a short time a great friend, and to Rania for sharing working experiences and the everyday life in the lab.  ...  of the most probable protonation and tautomeric state at physiological pH, followed by automated, flexible docking and calculation of the binding affinity using 6D-QSAR. 177 The resulting binding affinities  ... 
doi:10.5451/unibas-004911623 fatcat:r2ac6jm65vbtlgfcnwyyi7u6cu

Application of computer-based methods to guide the development of novel sirtuin inhibitors - [kumulative Dissertation] [article]

Berin Karaman, Universitäts- Und Landesbibliothek Sachsen-Anhalt, Martin-Luther Universität, Sippl, Wolfgang, Prof. Dr., Schutkowski, Mike, Prof. Dr., Ecker, Gerhard, Prof. Dr.
2018
We determined a significant correlation between the binding free energy of the compounds estimated by MM-GBSA calculations and in vitro data.  ...  Due to the absence of the smSirt2 crystal structure, we generated a homology model (HM) for this enzyme and rationalize the binding interactions of the detected inhibitors by means of docking.  ...  Pathway methods such as Free Energy Perturbation (FEP) and Thermodynamic Integration (TI) methods [156, 157] Promising results have been obtained using the FEP and TI methods in the lead optimization  ... 
doi:10.25673/1595 fatcat:qdimyx3ravbozei52dydcu46pm

Molecular Mechanisms of Ion and Solute Interactions with Voltage-Gated Ion Channels [article]

Yibo Wang, University Of Calgary, University Of Calgary, Sergei Noskov
2016
However, relative permeabilities of organic ions still relate to the binding free energies of a single ion. We also investigated two engineered NaK mutants.  ...  Multi-ion effects such as dependence on the barriers and wells for permeant ion on the type of co-permeant ion were found to play a significant role in the selectivity signature of the channel as well.  ...  Comparison of PMFs and relative binding free energies. (A) Free energy profiles from US.  ... 
doi:10.11575/prism/26993 fatcat:5afzd544c5f6vg3fq52zuciehe
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