Kartograf: A Geometrically Accurate Atom Mapper for Hybrid-Topology Relative Free Energy Calculations

Ries, Benjamin; Alibay, Irfan; Swenson, David W. H.; Baumann, Hannah M.; Henry, Michael M.; Eastwood, James R. B.; Gowers, Richard J.

doi:10.1021/acs.jctc.3c01206

Cited by 2 publications

(2 citation statements)

References 103 publications

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“…This is similar to findings of our earlier work . In (RE-)EDS, the positions of the end states should remain overlaid for good sampling (see Figure S8 in the Supporting Information), ideally without the use of (distance) restraints. , The definition of hybrid topologies can be facilitated by using automated tools such as Kartograf …”

Section: Resultssupporting

confidence: 78%

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Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations

Champion,

Hünenberger,

Riniker

2024

J. Chem. Theory Comput.

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The majority of drug-like molecules contain at least one ionizable group, and many common drug scaffolds are subject to tautomeric equilibria. Thus, these compounds are found in a mixture of protonation and/or tautomeric states at physiological pH. Intrinsically, standard classical molecular dynamics (MD) simulations cannot describe such equilibria between states, which negatively impacts the prediction of key molecular properties in silico. Following the formalism described by de Oliveira and co-workers (J. Chem. Theory Comput. 2019, 15, 424–435) to consider the influence of all states on the binding process based on alchemical free-energy calculations, we demonstrate in this work that the multistate method replica-exchange enveloping distribution sampling (RE-EDS) is well suited to describe molecules with multiple protonation and/or tautomeric states in a single simulation. We apply our methodology to a series of eight inhibitors of factor Xa with two protonation states and a series of eight inhibitors of glycogen synthase kinase 3β (GSK3β) with two tautomeric states. In particular, we show that given a sufficient phase-space overlap between the states, RE-EDS is computationally more efficient than standard pairwise free-energy methods.

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Section: Resultssupporting

confidence: 78%

“… 110 , 111 The definition of hybrid topologies can be facilitated by using automated tools such as Kartograf. 112 …”

Section: Resultsmentioning

confidence: 99%

Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations

Champion,

Hünenberger,

Riniker

2024

J. Chem. Theory Comput.

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Alchemical Transformations and Beyond: Recent Advances and Real-World Applications of Free Energy Calculations in Drug Discovery

Qian,

Xue,

et al. 2024

J. Chem. Inf. Model.

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Computational methods constitute efficient strategies for screening and optimizing potential drug molecules. A critical factor in this process is the binding affinity between candidate molecules and targets, quantified as binding free energy. Among various estimation methods, alchemical transformation methods stand out for their theoretical rigor. Despite challenges in force field accuracy and sampling efficiency, advancements in algorithms, software, and hardware have increased the application of free energy perturbation (FEP) calculations in the pharmaceutical industry. Here, we review the practical applications of FEP in drug discovery projects since 2018, covering both ligand-centric and residue-centric transformations. We show that relative binding free energy calculations have steadily achieved chemical accuracy in real-world applications. In addition, we discuss alternative physics-based simulation methods and the incorporation of deep learning into free energy calculations.

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Kartograf: A Geometrically Accurate Atom Mapper for Hybrid-Topology Relative Free Energy Calculations

Cited by 2 publications

References 103 publications

Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations

Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations

Alchemical Transformations and Beyond: Recent Advances and Real-World Applications of Free Energy Calculations in Drug Discovery

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