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Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.ORCID iD: 0000-0002-8880-9247
Univ Gothenburg, Dept Chem & Mol Biol, Kemivagen 10, SE-41296 Gothenburg, Sweden.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.ORCID iD: 0000-0001-9882-2018
Johnson & Johnson Innovat, Med Chem, One Chapel Pl, London W1G 0BG, England.
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2018 (English)In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 9, p. 11742-11757Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2018. Vol. 3, no 9, p. 11742-11757
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-368119DOI: 10.1021/acsomega.8b01379ISI: 000446186000140PubMedID: 30320271OAI: oai:DiVA.org:uu-368119DiVA, id: diva2:1267618
Funder
Swedish Research Council, 2016-05160Swedish Research Council, 2016-03602Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2018-12-03Bibliographically approved

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Poongavanam, VasanthanathanPeintner, StefanErdélyi, MátéKihlberg, Jan

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