Target–ligand binding affinity from single point enthalpy calculation and elemental composition

Literature Information

Publication Date 2023-11-03
DOI 10.1039/D3CP04483A
Impact Factor 3.676
Authors

Viktor Szél, Balázs Zoltán Zsidó, Norbert Jeszenői, Csaba Hetényi


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Abstract

Reliable target–ligand binding thermodynamics data are essential for successful drug design and molecular engineering projects. Besides experimental methods, a number of theoretical approaches have been introduced for the generation of binding thermodynamics data. However, available approaches often neglect electronic effects or explicit water molecules influencing target–ligand interactions. To handle electronic effects within a reasonable time frame, we introduce a fast calculator QMH-L using a single target–ligand complex structure pre-optimized at the molecular mechanics level. QMH-L is composed of the semi-empirical quantum mechanics calculation of binding enthalpy with predicted explicit water molecules at the complex interface, and a simple descriptor based on the elemental composition of the ligand. QMH-L estimates the target–ligand binding free energy with a root mean square error (RMSE) of 0.94 kcal mol−1. The calculations also provide binding enthalpy values and they were compared with experimental binding thermodynamics data collected from the most reliable isothermal titration calorimetry studies of systems including various protein targets and challenging, large peptide ligands with a molecular weight of up to 2–3 thousand. The single point enthalpy calculations of QMH-L require modest computational resources and are based on short runs with open source and/or free software like Gromacs, Mopac, MobyWat, and Fragmenter. QMH-L can be applied for fast, automated scoring of drug candidates during a virtual screen, enthalpic engineering of new ligands or thermodynamic explanation of complex interactions.

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Source Journal

Physical Chemistry Chemical Physics

Physical Chemistry Chemical Physics
CiteScore: 5.5
Self-citation Rate: 10.3%
Articles per Year: 3036

Physical Chemistry Chemical Physics (PCCP) is an international journal co-owned by 19 physical chemistry and physics societies from around the world. This journal publishes original, cutting-edge research in physical chemistry, chemical physics and biophysical chemistry. To be suitable for publication in PCCP, articles must include significant innovation and/or insight into physical chemistry; this is the most important criterion that reviewers and Editors will judge against when evaluating submissions. The journal has a broad scope and welcomes contributions spanning experiment, theory, computation and data science. Topical coverage includes spectroscopy, dynamics, kinetics, statistical mechanics, thermodynamics, electrochemistry, catalysis, surface science, quantum mechanics, quantum computing and machine learning. Interdisciplinary research areas such as polymers and soft matter, materials, nanoscience, energy, surfaces/interfaces, and biophysical chemistry are welcomed if they demonstrate significant innovation and/or insight into physical chemistry. Joined experimental/theoretical studies are particularly appreciated when complementary and based on up-to-date approaches.

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