Alchemical Free Energy Workflows for the Computation of Protein-Ligand Binding Affinities. 2024

Anna M Herz, and Tahsin Kellici, and Inaki Morao, and Julien Michel
EaStChem School of Chemistry, Joseph Black Building, University of Edinburgh, Edinburgh, UK.

Alchemical free energy methods can be used for the efficient computation of relative binding free energies during preclinical drug discovery stages. In recent years, this has been facilitated further by the implementation of workflows that enable non-experts to quickly and consistently set up the required simulations. Given the correct input structures, workflows handle the difficult aspects of setting up perturbations, including consistently defining the perturbable molecule, its atom mapping and topology generation, perturbation network generation, running of the simulations via different sampling methods, and analysis of the results. Different academic and commercial workflows are discussed, including FEW, FESetup, FEPrepare, CHARMM-GUI, Transformato, PMX, QLigFEP, TIES, ProFESSA, PyAutoFEP, BioSimSpace, FEP+, Flare, and Orion. These workflows differ in various aspects, such as mapping algorithms or enhanced sampling methods. Some workflows can accommodate more than one molecular dynamics (MD) engine and use external libraries for tasks. Differences between workflows can present advantages for different use cases, however a lack of interoperability of the workflows' components hinders systematic comparisons.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D000465 Algorithms A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. Algorithm
D012420 Running An activity in which the body is propelled by moving the legs rapidly. Running is performed at a moderate to rapid pace and should be differentiated from JOGGING, which is performed at a much slower pace. Runnings
D055808 Drug Discovery The process of finding chemicals for potential therapeutic use. Drug Prospecting,Discovery, Drug,Prospecting, Drug
D057188 Workflow Description of pattern of recurrent functions or procedures frequently found in organizational processes, such as notification, decision, and action. Work Flow,Work Flows,Workflows

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