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Prediction of Chameleonic Efficiency
Laurent David ; Mark Wenlock ; Patrick Barton , et al. ChemMedChem,2021,16(17):2669-2685. DOI: 10.26434/chemrxiv.14748879.v1 PubMed ID: 34240561
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Abstract: Chameleonic properties, i.e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeabilily and solubility for drug molecules with high MW.We present models ofexperimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113)and one PROTAC(MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics, A linearregression model that predicts chromatographic apparent polarity(EPSA) with a mean unsigned error of 10 A2 was derived based on separate terms for donor, acceptor, and tolal molecular SASA. A good correlation (R'0.92) with an experimental measure of hydrogen bond donor potential, Alog Poa, was found for the mean hydrogenbond donor SASA of the confommational ensemblescaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficlency indices, are introduced. We envislon that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeabilily and solubility.
Keywords: chameleonic properties ; polar surface area ; hydrogen bonding ; molecular dynamics
Purchased from AmBeed: 1257044-40-8 ; 198904-31-3 ; 173334-57-1 ; 1190307-88-0
CAS No. : | 1257044-40-8 | MDL No. : | MFCD23160052 |
Formula : | C45H50ClN7O7S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LQBVNQSMGBZMKD-UHFFFAOYSA-N |
M.W : | 868.44 | Pubchem ID : | 49846579 |
Synonyms : |
ABT-199;GDC-0199;RG 7601. Venetoclax.;RG7601
|
Chemical Name : | 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P202-P260-P301+P312-P302+P352-P305+P351+P338-P308+P313 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H361-H373 | Packing Group: | N/A |
GHS Pictogram: |