Details

Autor(en) / Beteiligte

• Khalak, Y
• Tresadern, G
• Aldeghi, M
• Baumann, H. M
• Mobley, D. L
• de Groot, B. L
• Gapsys, V

Titel

Alchemical absolute protein-ligand binding free energies for drug design

Ist Teil von

• Chemical science (Cambridge), 2021-10, Vol.12 (41), p.13958-13971

Ort / Verlag

England: Royal Society of Chemistry

Erscheinungsjahr

2021

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based absolute binding free energy estimates for 128 pharmaceutically relevant targets. We use a novel rigorous method to generate protein-ligand ensembles for the ligand in its decoupled state. Not only do the calculations deliver accurate protein-ligand binding affinity estimates, but they also provide detailed physical insight into the structural determinants of binding. We identify subtle rotamer rearrangements between apo and holo states of a protein that are crucial for binding. When compared to relative binding free energy calculations, obtaining absolute binding free energies is considerably more challenging in large part due to the need to explicitly account for the protein in its apo state. In this work we present several approaches to obtain apo state ensembles for accurate absolute Δ G calculations, thus outlining protocols for prospective application of the methods for drug discovery. Molecular dynamics based absolute protein-ligand binding free energies can be calculated accurately and at large scale to facilitate drug discovery.