INTRODUCTION - Prestwick Chemical2016/08/12 · PCL is delivered with a fully- annotated database....
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PCL is delivered with a fully- annotated database. Clearly the PCL has been designed to reduce the risk of "low quality" hits and is worldwide recognized for its excellence. Jean-Marie Contreras, 1 Laurent Schaeffer, 1 Christophe Morice, 1 Laurence Jung, 1 Jean-Marc Simon, 1 Marie-Louise Jung, 1 and Bruno Didier 2 1. Prestwick Chemical, 220 Blvd Gonthier d'Andernach, 67400 Illkirch, FRANCE 2. University of Strasbourg, Therapeutic Innovation Laboratory, UMR7200 CNRS, Faculty of Pharmacy, 74 route du Rhin, 67400 Illkirch, FRANCE 1. Drug Discov. Today 2005, 10, 987-992. 2. Curr. Opin. Chem. Biol. 2004, 3,:255-63. 3. Nucleic Acids Res., 2014, Vol. 42, Database issue D1083–D1090. 4. MIMS Drug Information System, Search Drug Information, Interactions, Images, Dosages & Side Effects. https://www.mims.com/. 5. WIPO - World Intellectual Property Organization. www.wipo.int/. 6. Vidal. http://www.vidal.fr/. 7. ACS Chem. Neurosci. 2010, 1, 435-449 8. Adv. Drug Delivery Rev. 1997, 23, 3-25. 9. TAKTIC (TrAnslational Kinase Tumor Inhibitor discovery Consortium) is a FP7-SME-2012 project (Grant number: 315746). 10. Neuromuscular Disorders, 2004, 14, 365-370. 11. Clinical Cancer Res., 2006, 12, 5557-5569. 12. Chem. Biol., 2005, 12, 973–980. 13. PNAS 2008, 105, 11218-11223. 14. PloS One 2008, 3, 1981. 15. J Virol. 2009, 83, 5148-5155. 16. J. Biol. Chem. 2009 284, 9394–9401. 17. Bioorg. Med. Chem. Let. 2009, 19, 1592–1595. 18. PloS One, 2012, 7, 1-14. It is commonly recognized that the quality of screening libraries has a crucial impact on the hit rate and on the pertinence of the obtained hits. In order to guarantee to customers a high level of performance, Prestwick Chemical has developed and offers a range of specific and valuable libraries for screening. Designed to ensure high-quality hits, they are focused on specific applications. The Prestwick Drug-Fragment Library (983 compounds) is dedicated to fragment based drug discovery (FBDD). The Prestwick CNS Drug Library (320 compounds) is recommended for performing screening on central nervous system (CNS) targets. Eventually, since more than 15 years, the Prestwick Chemical Library ® (PCL) is a collection of 1280 off-patent drugs especially designed for repositioning, assay validation, and hit discovery. The main specificities and advantages of these libraries will be discussed in the present poster. INTRODUCTION CONCLUSION & PERSPECTIVES REFERENCES PRESTWICK DRUG - FRAGMENT LIBRARY The Prestwick Drug-Fragment Library is a collection of compounds arising from smart fragmentation of 1565 off-patent approved drugs. The fragmentation process was performed manually, based on our expertise in medicinal chemistry. Each compound was carefully “cut” in relevant subunits following a precise methodology: from greatest to smallest fragment, realistic and pertinent bond disconnection, preservation of functional groups providing possible interactions. As a result of this formal exercise and after removal of the duplicates, 3166 fragments were generated. At this level, only synthetically accessible compounds were retained leading to a set of 2000 unique fragments. Finally by applying the well-established “rule of three” criteria, 1 984 original fragments were selected. PRESTWICK CHEMICAL LIBRARY ® (PCL) The Prestwick Chemical libraries are delivered with a fully-annotated database available in several electronic formats (SDF, XLS, DB, DWAR). The databases include information such as structure, chemical name, literature reference, physicochemical properties, targets, therapeutic class and effect, pharmacokinetics data and reported side effects as well as patent and ADME Tox issues. They have been recently highly updated by using several public sources. 3-6 FORMATS AND DATABASE The PCL is a powerful tool for any type of screening and for hit discovery. It is a collection of 1280 off-patent approved drugs selected for their high chemical and pharmacological diversity. Analysis of their physicochemical properties shows that 83% of the library compounds match with Lipinski drug-like parameters. 8 Half of the compounds respect Hann and Oprea lead-like parameters. 2 From a pharmacological point of view, a majority of the drugs within the library are dedicated to CNS, cardiovascular, metabolism and infectious diseases. Most of the targets are related to enzymes and GPCRs. The 1280 compounds of the library are known to have major effect on 256 single targets. One third of these targets are represented in the library by at least 3 ligand compounds. All the bioavailability and safety data in humans have been extensively described and the N N H O O H CF 3 N H 2 CF 3 N N H O O H N N H N NH 2 O O H N N N H N F O N N NH 2 F N H 2 N O Flunixin Prestw-Frag-1191 Prestw-Frag-1192 Prestw-Frag-1189 Prestw-Frag-0721 Astemizole Prestw-Frag-1051 Prestw-Frag-1050 1565 approved drugs 3595 fragments 3166 fragments 984 fragments Fragmentation process 1) Duplicates removal 2) Chemical availibility Rule of 3 2000 fragments Parameters Ro3 Criteria Range of value Average value MW ≤ 300 80 – 292 174.59 clogP ≤ 3 -2.0 – 2.9 1.52 HBD ≤ 3 0 – 3 1.11 HBA ≤ 3 0 – 3 2.17 Rot. bond ≤ 3 0 – 3 1.48 TPSA ≤ 60 3.24 – 104.06 42.33 Heavy atom ≤ 16 6 – 21 12.40 In order to verify the high occurrence of these fragments in new drugs, 119 compounds recently approved by the FDA and not included in the set of 1565 drugs initially fragmented were analyzed. 86% of them have at least one fragment present among our selection of 984 compounds. This underlines the spectacular occurrence of these fragments in drugs over time and their pertinence for FBDD. The Prestwick CNS Drug Library is a unique collection of 320 approved and marketed drugs carefully selected by a pharmacist/chemist team for their known pharmacological effects on the central nervous system. These compounds present a high degree of diversity in terms of therapeutic and biological targets. PRESTWICK CNS DRUG LIBRARY <3 3-4 4-5 5-6 5 32 96 187 MPO SCORE DISTRIBUTION Carrier 11% Enzyme 25% GPCR 38% Ion channel 4% Ionotropic receptor 7% Miscellaneous 15% TARGET TYPE DISTRIBUTION Analgesic Anesthetic Anticonvulsant Antidepressant Antiemetic Antihistaminic Antimigraine Anti-inflammatory Anti-Alzheimer Antiparkinsonian Antipsychotic Antipyretic Antispastic Antitussive Anxiolytic CNS stimulant Muscle relaxant Sedative THERAPEUTIC EFFECT DISTRIBUTION The set of retained fragments presents optimal physchem properties 2 as well as good MW and clogP distributions. 7 52 209 324 199 126 53 13 90 120 150 180 210 240 270 300 1 10 41 232 372 327 -2 -1 0 1 2 3 4 hits Hit rate: 0.02% 20 hits Hit rate: 1.56% no hit 3 Hits 25 032 4 HTS inactive cpds IC50 < 100 μM 1 260 20 PCL inactive cpds IC50 < 100 μM IC 50 < 10 μM IC 50 < 10 μM In the course of a hit discovery project (TAKTIC 9 ), a primary screening was performed to identify new inhibitors of NF-ĸB-inducing kinase (NIK), a serine/threonine protein kinase. A HTS approach using a commercial chemical database of 25K cpds considered to be highly diverse was compared with the use of a smart library. The PCL was clearly more favorable and efficient than an HTS library with a hit rate of 1.56% and with a higher number of micromolar inhibitors. Carrier 5% Enzyme 36% GPCR 27% Ion channel 7% Ionotropic receptor 4% Miscellaneous 21% TARGET TYPE DISTRIBUTION 119 drugs recently approved (2011-2015) 103 drugs containing at least one fragment among the 984 fragments of our library Based on its expertise in medicinal chemistry, Prestwick Chemical has developed smart and valuable tools for high quality screening. The Prestwick Drug-Fragment Library has been designed in order to propose a set of original fragments having high occurrence in approved drugs, including the most recent. This powerful approach is also transposable to other research fields (agrochemistry, animal health, cosmetics). Moreover, the Prestwick CNS Drug Library derives its interest from known CNS activity and applications, while others competitors CNS libraries are based on calculated physchem properties. Eventually, the PCL, through its large degree of chemical and pharmacological diversity, has demonstrated over the past 17 years a high efficiency for identification of new hits and characterization of biochemical mechanisms. 10-18 CNS MPO (Central Nervous System Multiparameter Optimization) score 7 is above 4 for more than 88% of the compounds, confirming the clinical indications and the interest of this library as appropriate tool to accelerate lead discovery in the CNS field. Prestwick Drug- Fragment Library 984 fragments 49% 16% 35% NUMBER OF DRUGS PER TARGET 1 drug 2 drugs ≥3 drugs 256 TARGETS MW VS CLOGP CORRELATION EXAMPLES OF FRAGMENTED DRUGS CLOGP MOLECULAR WEIGHT PHYSCHEM ANALYSIS OF THE 983 FRAGMENTS LIBRARY IN MEMORIAM Professor Camille G. WERMUTH (1933-2015) Emeritus Professor of organic and medicinal chemistry at the Faculty of Pharmacy of Strasbourg, Founder of Prestwick Chemical and editor of the famous book “The Practice of Medicinal Chemistry”.
Transcript of INTRODUCTION - Prestwick Chemical2016/08/12 · PCL is delivered with a fully- annotated database....
PCL is delivered with a fully-annotated database. Clearly thePCL has been designed to reducethe risk of "low quality" hits and isworldwide recognized for itsexcellence.
Jean-Marie Contreras,1 Laurent Schaeffer,1 Christophe Morice,1 Laurence Jung,1 Jean-Marc Simon,1
Marie-Louise Jung,1 and Bruno Didier2
1. Prestwick Chemical, 220 Blvd Gonthier d'Andernach, 67400 Illkirch, FRANCE2. University of Strasbourg, Therapeutic Innovation Laboratory, UMR7200 CNRS, Faculty of Pharmacy, 74 route du Rhin, 67400 Illkirch, FRANCE
1. Drug Discov. Today 2005, 10, 987-992. 2. Curr. Opin. Chem. Biol. 2004, 3,:255-63. 3. Nucleic Acids Res., 2014, Vol. 42, Database issue D1083–D1090. 4. MIMS DrugInformation System, Search Drug Information, Interactions, Images, Dosages & Side Effects. https://www.mims.com/. 5. WIPO - World Intellectual Property Organization.www.wipo.int/. 6. Vidal. http://www.vidal.fr/. 7. ACS Chem. Neurosci. 2010, 1, 435-449 8. Adv. Drug Delivery Rev. 1997, 23, 3-25. 9. TAKTIC (TrAnslational Kinase TumorInhibitor discovery Consortium) is a FP7-SME-2012 project (Grant number: 315746). 10. Neuromuscular Disorders, 2004, 14, 365-370. 11. Clinical Cancer Res., 2006, 12,5557-5569. 12. Chem. Biol., 2005, 12, 973–980. 13. PNAS 2008, 105, 11218-11223. 14. PloS One 2008, 3, 1981. 15. J Virol. 2009, 83, 5148-5155. 16. J. Biol. Chem. 2009284, 9394–9401. 17. Bioorg. Med. Chem. Let. 2009, 19, 1592–1595. 18. PloS One, 2012, 7, 1-14.
It is commonly recognized that the quality of screening libraries has a crucial impact on the hit rate and on the pertinence of the obtained hits. In order to guarantee tocustomers a high level of performance, Prestwick Chemical has developed and offers a range of specific and valuable libraries for screening. Designed to ensure high-qualityhits, they are focused on specific applications. The Prestwick Drug-Fragment Library (983 compounds) is dedicated to fragment based drug discovery (FBDD). The PrestwickCNS Drug Library (320 compounds) is recommended for performing screening on central nervous system (CNS) targets. Eventually, since more than 15 years, the PrestwickChemical Library® (PCL) is a collection of 1280 off-patent drugs especially designed for repositioning, assay validation, and hit discovery. The main specificities andadvantages of these libraries will be discussed in the present poster.
INTRODUCTION
CONCLUSION & PERSPECTIVES
REFERENCES
PRESTWICK DRUG-FRAGMENT LIBRARY
The Prestwick Drug-Fragment Library is a collection of compounds arising fromsmart fragmentation of 1565 off-patent approved drugs. The fragmentationprocess was performed manually, based on our expertise in medicinal chemistry.Each compound was carefully “cut” in relevant subunits following a precisemethodology: from greatest to smallest fragment, realistic and pertinent bonddisconnection, preservation of functional groups providing possible interactions.As a result of this formal exercise and after removal of the duplicates, 3166fragments were generated. At this level, only synthetically accessible compoundswere retained leading to a set of 2000 unique fragments. Finally by applying thewell-established “rule of three” criteria,1 984 original fragments were selected.
PRESTWICK CHEMICAL LIBRARY® (PCL)
The Prestwick Chemical libraries aredelivered with a fully-annotated databaseavailable in several electronic formats (SDF,XLS, DB, DWAR). The databases includeinformation such as structure, chemicalname, literature reference, physicochemicalproperties, targets, therapeutic class andeffect, pharmacokinetics data and reportedside effects as well as patent and ADME Toxissues. They have been recently highlyupdated by using several public sources.3-6
FORMATS AND DATABASE
The PCL is a powerful tool for any type of screening and for hit discovery. It is acollection of 1280 off-patent approved drugs selected for their high chemical andpharmacological diversity. Analysis of their physicochemical properties shows that83% of the library compounds match with Lipinski drug-like parameters.8 Half ofthe compounds respect Hann and Oprea lead-like parameters.2 From apharmacological point of view, a majority of the drugs within the library arededicated to CNS, cardiovascular, metabolism and infectious diseases. Most of thetargets are related to enzymes and GPCRs. The 1280 compounds of the libraryare known to have major effect on 256 single targets. One third of these targetsare represented in the library by at least 3 ligand compounds. All thebioavailability and safety data in humans have been extensively described and the
N
NH
OOH
CF3 NH
2CF
3
N
NH
OOH
N
NH
N
NH2
OOH
N
NNH
N
F
ON
NNH
2
F
NH2
N
O
Flunixin Prestw-Frag-1191 Prestw-Frag-1192 Prestw-Frag-1189Prestw-Frag-0721
Astemizole Prestw-Frag-1051Prestw-Frag-1050
1565 approved drugs 3595 fragments3166 fragments
984 fragments
Fragmentationprocess
1) Duplicates removal2) Chemical availibility Rule of 3
2000 fragments
Parameters Ro3 Criteria Range of value Average value
MW ≤ 300 80 – 292 174.59
clogP ≤ 3 -2.0 – 2.9 1.52
HBD ≤ 3 0 – 3 1.11
HBA ≤ 3 0 – 3 2.17
Rot. bond ≤ 3 0 – 3 1.48
TPSA ≤ 60 3.24 – 104.06 42.33
Heavy atom ≤ 16 6 – 21 12.40
In order to verify the high occurrence ofthese fragments in new drugs, 119compounds recently approved by the FDAand not included in the set of 1565 drugsinitially fragmented were analyzed. 86% ofthem have at least one fragment presentamong our selection of 984 compounds.This underlines the spectacular occurrenceof these fragments in drugs over time andtheir pertinence for FBDD.
The Prestwick CNS Drug Library is a unique collection of 320 approved andmarketed drugs carefully selected by a pharmacist/chemist team for their knownpharmacological effects on the central nervous system. These compounds presenta high degree of diversity in terms of therapeutic and biological targets.
PRESTWICK CNS DRUG LIBRARY
<3 3-4 4-5 5-6
532
96
187
MPO SCORE DISTRIBUTION
Carrier 11%
Enzyme 25%
GPCR 38%
Ion channel4%
Ionotropic receptor 7%
Miscellaneous 15%
TARGET TYPE DISTRIBUTION
Analgesic
Anesthetic
Anticonvulsant
Antidepressant
Antiemetic
Antihistaminic
AntimigraineAnti-inflammatory
Anti-AlzheimerAntiparkinsonian
Antipsychotic
Antipyretic
Antispastic
Antitussive
Anxiolytic
CNS stimulant
Muscle relaxant Sedative
THERAPEUTIC EFFECT DISTRIBUTION
The set of retained fragments presents optimal physchem properties2 as well asgood MW and clogP distributions.
752
209
324
199
126
5313
90 120 150 180 210 240 270 300
1 10 41
232
372
327
-2 -1 0 1 2 3
4 hitsHit rate: 0.02%
20 hitsHit rate: 1.56%
no hit 3 Hits
25 032
4
HTS
inactive cpds IC50 < 100 µM
1 260
20
PCL
inactive cpds IC50 < 100 µM
IC50 < 10 µM IC50 < 10 µM
In the course of a hit discoveryproject (TAKTIC9), a primaryscreening was performed to identifynew inhibitors of NF-ĸB-inducingkinase (NIK), a serine/threonineprotein kinase. A HTS approachusing a commercial chemicaldatabase of 25K cpds considered tobe highly diverse was comparedwith the use of a smart library. ThePCL was clearly more favorable andefficient than an HTS library with ahit rate of 1.56% and with a highernumber of micromolar inhibitors.
Carrier 5%
Enzyme 36%
GPCR 27%
Ion channel 7%
Ionotropic receptor 4%
Miscellaneous 21%
TARGET TYPE DISTRIBUTION
119 drugs recently approved (2011-2015)
103 drugs containing at least
one fragment among the 984
fragments of our library
Based on its expertise in medicinal chemistry, Prestwick Chemical has developedsmart and valuable tools for high quality screening. The Prestwick Drug-FragmentLibrary has been designed in order to propose a set of original fragments havinghigh occurrence in approved drugs, including the most recent. This powerfulapproach is also transposable to other research fields (agrochemistry, animalhealth, cosmetics). Moreover, the Prestwick CNS Drug Library derives its interestfrom known CNS activity and applications, while others competitors CNS librariesare based on calculated physchem properties. Eventually, the PCL, through itslarge degree of chemical and pharmacological diversity, has demonstrated overthe past 17 years a high efficiency for identification of new hits andcharacterization of biochemical mechanisms.10-18
CNS MPO (Central Nervous System MultiparameterOptimization) score7 is above 4 for more than 88% ofthe compounds, confirming the clinical indications andthe interest of this library as appropriate tool toaccelerate lead discovery in the CNS field.
Prestwick Drug-Fragment Library
984 fragments
49%
16%
35%
NUMBER OF DRUGSPER TARGET
1 drug
2 drugs
≥3 drugs
256TARGETS
MW VS CLOGP CORRELATION
EXAMPLES OF FRAGMENTED DRUGS
CLOGPMOLECULAR WEIGHTPHYSCHEM ANALYSIS OF THE 983 FRAGMENTS LIBRARY
IN MEMORIAM
Professor Camille G. WERMUTH(1933-2015)
Emeritus Professor of organic andmedicinal chemistry at the Facultyof Pharmacy of Strasbourg, Founderof Prestwick Chemical and editor ofthe famous book “The Practice ofMedicinal Chemistry”.
