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Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?

Journal article
Authors V. Poongavanam
Emma Danelius
S. Peintner
L. Alcaraz
G. Caron
M. D. Cummings
S. Wlodek
Mate Erdelyi
P. C. D. Hawkins
G. Ermondi
J. Kihlberg
Published in Acs Omega
Volume 3
Issue 9
Pages 11742-11757
ISSN 2470-1343
Publication year 2018
Published at Swedish NMR Centre at Göteborg University
Department of Chemistry and Molecular Biology
Pages 11742-11757
Language en
Keywords protein-protein interaction, polar surface-area, clinical candidates, erythromycin-a, beta-hairpins, force-field, nmr data, discovery, rule, permeability, Chemistry, ill wc, 1990, journal of the american chemical society, v112, p6127
Subject categories Clinical Medicine


Conformational flexibility is a major determinant of the properties of macrocycles and other drugs in beyond rule of 5 (bRo5) space. Prediction of conforrriations is essential for design of drugs in this space, and we have evaluated three tools for conformational sampling of la set of 10 bRo5 drugs and clinical candidates in polar and apolar environments. The distance-geometry based OMEGA was found to yield ensembles spanning larger structure and property spaces than the ensembles obtained by MOE LowModeMD (MOE) and MacroModel (MC). Both MC and OMEGA but not MOE generated different ensembles for polar and apolar environments. All three conforinational search methods generated conformers similar to the crystal structure conformers for 9 of the 10 compounds, with OMEGA performing somewhat better than MOE and MC. MOE and OMEGA found all six conformers of roxithromycin that were identified by NMR in aqueous solutions, whereas only OMEGA sampled the three conformers observed in chloroform. We suggest that characterization of conformers using molecular descriptors, e.g., the radius of gyration and polar surface area, is preferred to energy- or root-mean-square deviation-based methods for selection of biologically relevant conformers in drug discovery in bRo5 space.

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