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Conformational Samp...
Conformational Sampling of Macrocyclic Drugs in Different Environments: Can We Find the Relevant Conformations?
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- Poongavanam, Vasanthanathan (författare)
- Uppsala universitet,Organisk kemi
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- Danelius, Emma (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology,Univ Gothenburg, Dept Chem & Mol Biol, Kemivagen 10, SE-41296 Gothenburg, Sweden
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- Peintner, Stefan, 1991- (författare)
- Uppsala universitet,Organisk kemi
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- Alcaraz, L. (författare)
- Johnson & Johnson Innovat, Med Chem, One Chapel Pl, London W1G 0BG, England
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- Caron, G. (författare)
- Univ Torino, Dept Mol Biotechnol & Hlth Sci, Quarello 15, I-10135 Turin, Italy
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- Cummings, M. D. (författare)
- Janssen Res & Dev, 1400 McKean Rd, Spring House, PA 19477 USA
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- Wlodek, S. (författare)
- OpenEye Sci Software, 9 Bisbee Court, Santa Fe, NM 87508 USA
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- Erdelyi, Mate, 1975 (författare)
- Uppsala universitet,Gothenburg University,Göteborgs universitet,Svenskt NMR-centrum vid Göteborgs universitet,Swedish NMR Centre at Göteborg University,Organisk kemi,Swedish NMR Ctr, Medicinaregatan 5, SE-40530 Gothenburg, Sweden
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- Hawkins, P. C. D. (författare)
- OpenEye Sci Software, 9 Bisbee Court, Santa Fe, NM 87508 USA
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- Ermondi, G. (författare)
- Univ Torino, Dept Mol Biotechnol & Hlth Sci, Quarello 15, I-10135 Turin, Italy
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- Kihlberg, Jan (författare)
- Uppsala universitet,Organisk kemi
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(creator_code:org_t)
- 2018-09-24
- 2018
- Engelska.
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Ingår i: Acs Omega. - : American Chemical Society (ACS). - 2470-1343. ; 3:9, s. 11742-11757
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Nyckelord
- 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
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Poongavanam, Vas ...
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Danelius, Emma
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Peintner, Stefan ...
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Alcaraz, L.
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Caron, G.
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Cummings, M. D.
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visa fler...
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Wlodek, S.
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Erdelyi, Mate, 1 ...
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Hawkins, P. C. D ...
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Ermondi, G.
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Kihlberg, Jan
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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- NATURVETENSKAP
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NATURVETENSKAP
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och Biologi
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och Biokemi och mole ...
- Artiklar i publikationen
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Acs Omega
- Av lärosätet
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Göteborgs universitet
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Uppsala universitet