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 H nuclear magnetic resonance (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 analogs. Prioritizing design ideas, based on calculations and analysis of measurements across a series, efficiently guides rational discovery towards the "right molecules" for effective medicines.
Highlights
Nuclear magnetic resonance (NMR) signal line shapes inherently provide atomic-level, site-specific insights into structural dynamics
The fundamental concept of filtering theoretical conformations through experimental data to derive the best fit has become well established over the decades, together with variations in details of implementation, to determine the conformational preference(s) of a small molecule in solution (Cicero et al, 1995; Nevins et al, 1999; Slabber et al, 2016; Wu et al, 2017; Balazs et al, 2019; Farès et al, 2019; Atilaw et al, 2021)
A superimposition of histograms counting the number of times the particular bond was observed at any particular angle is plotted onto the rotational energy barrier plot showing the torsion potential at each dihedral angle, summarizing the conformational space sampled during the replica exchange with solute tempering molecular dynamics (REST-MD) simulation
Summary
Nuclear magnetic resonance (NMR) signal line shapes inherently provide atomic-level, site-specific insights into structural dynamics. The challenge is to conceive of ideas to modify the structure to discover a new molecule to favor this conformation Towards this aim of optimizing the free energy of binding, it is desirable for ligands in solution to preferentially pre-organize into the bioactive binding mode (Blundell et al, 2013; Balazs et al, 2019). Structure-based drug design (SBDD) can be enhanced by ready access to 3D free ligand average solution conformations to complement X-ray crystallographic models of the bound ligand and protein–ligand interactions (Blundell et al, 2013; Chiarparin et al, 2019; Balazs et al, 2019). The theoretical and experimental data complement each other: REST-MD simplifies the interpretation of NMR conformational dynamics, while the experimental NMR results can inform calculations by defining site-specific preferred torsions of the dominant conformer and experimental conformer distributions, which may influence the initial REST-MD 3D geometry and the sampling ergodicity achieved, as reflected in the resultant histograms
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