Evaluating the use of absolute binding free energy in the fragment optimisation process.

Autor: Alibay I; Department of Biochemistry, The University of Oxford, South Parks Road, OX1 3QU, Oxford, UK., Magarkar A; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an de Riß, Germany., Seeliger D; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an de Riß, Germany.; Exscientia Inc, Office 400E, 2125 Biscayne Blvd, Miami, FL, 33137, USA., Biggin PC; Department of Biochemistry, The University of Oxford, South Parks Road, OX1 3QU, Oxford, UK. philip.biggin@bioch.ox.ac.uk.
Jazyk: angličtina
Zdroj: Communications chemistry [Commun Chem] 2022 Sep 05; Vol. 5 (1), pp. 105. Date of Electronic Publication: 2022 Sep 05.
DOI: 10.1038/s42004-022-00721-4
Abstrakt: Key to the fragment optimisation process within drug design is the need to accurately capture the changes in affinity that are associated with a given set of chemical modifications. Due to the weakly binding nature of fragments, this has proven to be a challenging task, despite recent advancements in leveraging experimental and computational methods. In this work, we evaluate the use of Absolute Binding Free Energy (ABFE) calculations in guiding fragment optimisation decisions, retrospectively calculating binding free energies for 59 ligands across 4 fragment elaboration campaigns. We first demonstrate that ABFEs can be used to accurately rank fragment-sized binders with an overall Spearman's r of 0.89 and a Kendall τ of 0.67, although often deviating from experiment in absolute free energy values with an RMSE of 2.75 kcal/mol. We then also show that in several cases, retrospective fragment optimisation decisions can be supported by the ABFE calculations. Comparing against cheaper endpoint methods, namely N wat -MM/GBSA, we find that ABFEs offer better ranking power and correlation metrics. Our results indicate that ABFE calculations can usefully guide fragment elaborations to maximise affinity.
(© 2022. The Author(s).)
Databáze: MEDLINE
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