©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Properties predicted by COSMO-RS-based QSAR Dr. Karin Wichmann COSMOlogic GmbH & Co. KG Burscheider Str. 515 D Leverkusen Germany Phone: Fax: Web:

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Property Prediction with the -potential COSMOtherm allows for the prediction of the entire fluid phase equilibrium thermodynamics of almost arbitrary compounds, e.g: -Activity coefficients -Solubility -Partition coefficients between well characterized liquid phases The chemical potential and thermodynamic properties of liquids can easily be computed using the COSMO-RS -potential S ( ): e.g. activity coefficients X S :

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Treatment of complex or chemically less well-defined matrices Some physiological and thermodynamic equilibria involve phases or matrices which are -Chemically not well defined or of unknown composition -Disordered -Not really liquid / amorphous E.g. phases like -Biological tissues, blood, brain, the intestinal resorption system -Soap, polymers, cotton -Solid adsorbents like activated carbon -potential cannot be calculated directly by COSMO-RS

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Treatment of complex or chemically less well-defined matrices Chemically not well defined phases can be treated indirectly with the -moments: The -potential can be approximated very accurately by a set of functions M i X : -moments M i X are defined with: And Hydrogen Bonding moments M i,HB X M 0 X : molecular area M 1 X : negative total charge of compound X M 2 X : correlated with the screening energy for X M 3 X : skewness of the profile M -1/-2 X or M don/acc X : hydrogen bond capacity

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Treatment of complex or chemically less well-defined matrices With the -moments, -each phase / matrix can be characterized by a set of -coefficients c i S. -Differences between two phases can be described by the same kind of expansion, with coefficients c i S,S being the difference of the coefficients of the two phases. -Partition coefficients between two phases are generally expressed by a linear combination of the compounds -moments in the form:

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 QSPR applications -moments can be used as descriptors for linear QSAR/QSPR applications. Using COSMOtherm -moment descriptors it is possible to predict: -Partition behaviour between almost arbitrary phases, such as -CaCo2 cell permeability -logK BB blood-brain barrier partition -logK OC soil-water partitioning (environmental fate) -logK IA intestinal absorption -... and many more -Solubility of drugs in arbitrary solvents -Chemical potentials of crystal surfaces in solution morphology of drugs

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 QSPR applications -Only five -moments M i X are necessary to get a general QSPR description of solvents or biological matrices: -This is in correspondence with the general solvation theory of Abraham, which claims that solvent space is five-dimensional. -Intercorrelation of the COSMOtherm -moments and the Abraham set of solvent descriptors is possible* *Andreas M. Zissimos, Michael H. Abraham, Andreas Klamt, Frank Eckert, John Wood, J. Chem. Inf. Comput. Sci. 42 (2002) 1320

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Blood-Brain Partitioning logBB = M M M N = 103 rms = 0.41 R 2 = Exp. Data: Rose, K.; Hall, L. H.; Hall, L. M.; Kier, L. B. Modeling Blood-Brain Barrier Partitioning Using Topological Structure Descriptors, Elsevier MDL Web Site. (accessed Feb 13, 2004).

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Human Serum Albumin Binding logK HSA = M M M M 3,acc N = 94 rms = 0.33 R 2 = Exp. Data: Kier, L. B.; Hall, L. H.; Hall, L. M. QSAR Modeling of Drug Binding to Protein. -Lactam Serum Binding and Albumin Binding Affinity, Elsevier MDL Web Site. (accessed Oct 7, 2004).

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Intestinal Absorption logK HSA = M M M M 3,acc M 3,don

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Soil Sorption logK OC = M M M M 3,acc – 0.33 M 3,don N = 386 rms = 0.61 R 2 = 0.72

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Adsorption to Activated Carbon [Mehler, Peukert (TU München), Klamt; AICHE Journal. 48, (2002)]

©2009, COSMOlogic GmbH & Co KGCOSMO-RS Symposium 2009 Model of Cytochrome P450 2D6 and Cytochrome P450 3A4 Modelling inhibition of Cytochrome P450 2D6 using -moment descriptors for a diverse set of 33 compounds from the NCI database. Log(IC50) = 2.96(0.56) – (0.0018)*Area (0.0067)*sig (0.012)*sig (0.089)*HBacc (0.14)*HBdon3 Modelling inhibition of Cytochrome P450 3A4 using -moment descriptors for 45 structurally diverse drugs. (2 outliers deleted.) Log(IC50) = 4.46(0.50) – (0.0017)*Area (0.0078)*sig (0.010)*sig (0.128)*HBacc (0.14)*HBdon3 Dataset from Pharm. Res. 2003, 20, 1401.