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Physicochemical property based scoring scheme for design of an aminerg GPCR-targeted fragment library: The Fragment-GPCR-Score „ FrAGS ”. UGM Budapest 21st of may 2014 Adam A. Kelemen Hungarian Academy of Sciences Medicinal Chemistry Research Group.
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Physicochemical property based scoring scheme fordesign of an aminerg GPCR-targeted fragment library: The Fragment-GPCR-Score „FrAGS” UGM Budapest 21st of may 2014 Adam A. Kelemen Hungarian Academy of Sciences MedicinalChemistry Research Group
Introduction:G-Protein coupled receptors and the fragment-based drug discovery Fragment-based approach: Biophysical or biochemical screening of small-sized, simple, polar molecules in high-concentrations Aims of thestudy: Advantages: 1. Better sampling of the chemical space 2. Freedom in optimizing them to lead-molecules with favourable pharmacokinetic properties Establishment of a scoring scheme supporting the design of GPCR-targeted fragment libraries Characteristic: Screening at higher concentrations Rules for the scoring scheme are derived through: 1. data mining of an open access bioactivity database (ChEMBL)usingChemAxon’s Instant Jchem and Knime 2. Examination of physicochemical descriptors(well known from Rule of Three, Rule of Five)usingChemAxon’s JChemfor Excel Fragment-library design: 1. Scaled to the fragment-screening paradigm 2. Diversity (fragment chemical space: 107) G-protein coupled receptors, biology, localization: 1. Largest cell-membrane receptor family 2. Endogenous ligands: neurotransmitters, peptides, hormones 3. 7TM structure, extracellular N-terminal 4. 85% of GPCRs belongs to class A: (aminergic-, chemokine-, glycoprotein-hormone-, neuropeptide-) 5. Approx. 40% of marketed small molecule drugs are GPCR-targeted Stephen P. Andrews, ChemMedChem, 2014, 9, 256-275
Data Collection and preparation:Training Sets Reference (inactive) set Active set GPCRs ChEMBL GPCR SARfari(EBI, EMBL), Data mining with Instant Jchem and Konstanz Information Miner Class A 947914 entries: molecules,in vitro-essay data (binding, functional, ADME), GPCR-target Entire ChEMBL (active set subtracted) 1292344 entry Aminerg 1. Activity data: binding essay, IC50, logIC50, Ki, logKiconversion to pKi 2. species-independent data 3. Counter ions of salts stripped 4. 8 ≤ Nheavy ≤ 22 Muscarinic Achetylcholine, ACM[x] Adrenoceptors, α[x], β[x] Dopamine, DRD[x] Histamine, HRH[x] Serotonine, 5HT[x] Octopamine Trace Amine, TAAR[x] 1. Counter ions of salts stripped 2. 8 ≤ Nheavy ≤ 22 10477 fragments 309962 fragments 5000 random sampling Size-independent ligand efficiency: ≥ 1.95 on at least 4 GPCR-receptors • Rate of aminergic-dataintheactivesetderivedfromChEMBL GPCR-SARfari(2370 fragments): • 187 fragments contain at least 4 active data on only not-aminergic class-A receptors • Remaining 2183 fragments possess activity data only on aminergic GPCRs 2370 active fragments 2183 fragmentswithrelatedactivityonaminergic GPCR’s
RED: GPCR fragments BLUE: inactive reference set Calculation of physicochemical properties with JCHEM FOR EXCEL 1. Octanol:water partition coefficient (logP) 2. Octanol:water distribution coefficient (logD, pH = 7.4) 3. Polar Surface Area (PSA) 4. Rotatable Bond Count (nROT),5. Acceptor Count (HBA) 6. Donor Count (HBD) 6. Strongest acidic pKa 7. Strongest basic pKa 8. Number of Nitrogen Atoms 9. Number of Oxygen Atoms Base Acid Zwitterion Neutral
Results I. – Selection of GPCR Characteristic descriptors PolarSurfaceAreas(at pH = 7.4) of theactivefragmentshavetheirmedian and meanat lower values, than the reference set. logP, Donor Count and AcceptorCount distributions do not show significant difference between the compared sets, however the lower scores of the logD(calculated at pH = 7.4)showed, that GPCR-like fragments have mostlybasic character. 83% of the active fragments resulted to have basic character, 16% of the fragments were neutral. AminergicGPCR-activefragments constitute a set of: I. small sized II. rigidmolecules, III. containing few heteroatoms, IV. that are mostly(~83%) basic nitrogens.
results II. – Desirabilityfunctions and scoring (Fragmentgpcrscore) The desirability function maps the value of a property onto a score in the range of [0; 1]. FrAGS
Validation– ChemBL, PubChem, Fs, HTS 1. ChEMBLvalidationset 3. Richter Gedeon experimentalvalidationset 2183 actives/ 96539 inactives High-throughput and fragmentscreeningdataonaminergic GPCR targets 2. PubChemvalidationsets class-Atargeted HTS confirmedactiveswith at least 10 μM activity - screenings on allosteric-bindings- targeting β-arrestinpathways- or used as counter-screening were sorted out HTS validationset(onlyfragmentsize) 41 activefragments/ 9261 inactivefragments FS validationset: 33 activefragments / 3038 inactivefragments Targetsrepresentedin HTS campaigns: 5HT1A and 5HT1Ewith31confirmed activefragments TAAR1 with 169confirmed activefragments Serotonine receptor relatedvalidationset: 31 activefragments / 3100 inactivefragments Trace-amine receptor relatedset: 169 activefragments/ 16900 inactivefragments
SUmmary An active set of class-A aminerg-like fragments was extracted from ChemBL GPCR-SARfari Identification of aminerg-characteristic fragment properties Creation of a desirability-function based score (FrAGS – FragmentAminergic GPCR Score) Validation by using both public and proprietary experimental screening data (PubChem, RG) Further Plans Compilation of an in-house fragment library Use of FrAGS for the design of a GPCR-targeted fragment library Supplement of the in-house library by commercially available fragments and by synthesis