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Adapting free energy perturbation simulations for large macrocyclic ligands: how to dissect contributions from direct binding and free ligand flexibility

DOI: 10.1039/C9SC04705K DOI Help

Authors: Kerstin Wallraven (VU University Amsterdam) , Fredrik L. Holmelin (AstraZeneca) , Adrian Glas (VU University Amsterdam) , Sven Hennig (VU University Amsterdam) , Andrey I. Frolov (AstraZeneca) , Tom N. Grossmann (VU University Amsterdam)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chemical Science , VOL 11 , PAGES 2269 - 2276

State: Published (Approved)
Published: February 2020
Diamond Proposal Number(s): 19800

Open Access Open Access

Abstract: Large and flexible ligands gain increasing interest in the development of bioactive agents. They challenge the applicability of computational ligand optimization strategies originally developed for small molecules. Free energy perturbation (FEP) is often used for predicting binding affinities of small molecule ligands, however, its use for more complex ligands remains limited. Herein, we report the structure-based design of peptide macrocycles targeting the protein binding site of human adaptor protein 14-3-3. We observe a surprisingly strong dependency of binding affinities on relatively small variations in substituent size. FEP was performed to rationalize observed trends. To account for insufficient convergence of FEP, restrained calculations were performed and complemented with extensive REST MD simulations of the free ligands. These calculations revealed that changes in affinity originate both from altered direct interactions and conformational changes of the free ligand. In addition, MD simulations provided the basis to rationalize unexpected trends in ligand lipophilicity. We also verified the anticipated interaction site and binding mode for one of the high affinity ligands by X-ray crystallography. The introduced fully-atomistic simulation protocol can be used to rationalize the development of structurally complex ligands which will support future ligand maturation efforts.

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I04-Macromolecular Crystallography

Added On: 18/03/2020 11:32


Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)