Preprints
https://doi.org/10.5194/mr-2021-27
https://doi.org/10.5194/mr-2021-27

  12 Mar 2021

12 Mar 2021

Review status: this preprint is currently under review for the journal MR.

NMR free ligand conformations and atomic resolution dynamics

Amber Y. S. Balazs1, Nichola L. Davies2, David Longmire2, Martin J. Packer2, and Elisabetta Chiarparin2 Amber Y. S. Balazs et al.
  • 1Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States
  • 2Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0QA, United Kingdom

Abstract. Knowledge of free ligand conformational preferences (energy minima) and conformational dynamics (rotational energy barriers) of small molecules in solution can guide drug design hypotheses and help rank ideas to bias syntheses towards more active compounds. Visualization of conformational exchange dynamics around torsion angles, by replica-exchange with solute tempering molecular dynamics (REST-MD), gives results in agreement with high resolution 1H NMR spectra and complements free ligand conformational analyses. Rotational energy barriers around individual bonds are comparable between calculated and experimental values, making the in silico method relevant to ranking prospective design ideas in drug discovery programs, particularly across a series of analogues. Prioritizing design ideas, based on calculations and analysis of measurements across a series, efficiently guides rational discovery towards the right molecules for effective medicines.

Amber Y. S. Balazs et al.

Status: open (until 27 Apr 2021)

Comment types: AC – author | RC – referee | CC – community | EC – editor | CEC – chief editor | : Report abuse

Amber Y. S. Balazs et al.

Amber Y. S. Balazs et al.

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Short summary
In drug discovery, ready access to accurate atomic resolution information revealing conformations and dynamics of novel small molecules in solution guides rational design to optimize drug potency and physical chemistry. We developed an efficient integration of molecular dynamics calculations and visualization protocols with NMR conformational analysis of free ligands in solution. Agreement between experiment and theory inspires confidence in prospective computational analysis of new designs.