integrated drug discovery capabilities · 2020. 7. 22. · •target validation with a genetic and...
TRANSCRIPT
INTEGRATED
DRUG DISCOVERY
CAPABILITIES
Selvita Services
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• Target validation
• Hit identification
• Hit to lead
• Lead optimization
• Preclinical candidate nomination
• Broad target class and disease area expertise
• Quality Control
• Release Analyses
• Impurity Studies
• Method Development and Validation
• Synthesis process optimization
and parametrization
• Scale-up of processes
& technology transfers
• Custom synthesis of NCEs, impurities/
metabolites identification and synthesis
• Isotope labelling (2H, 13C, 15N)
• Computational chemistry
Drug discovery services Regulatory Research and development
Comparative studies of biosimilar
products
• Pharmacodynamic studies
• Crystallography
• Proliferation studies in vitro
• Metabolic studies in vitro
• Process related impurities measurement
Support for drug discovery in the areas of:
• Medicinal/Synthetic chemistry
• Assay development & screening
• In vitro pharmacology
• ADME/DMPK
• Protein production & crystallography
• CADD/ AI-driven drug discovery
Leading partner for Integrated Drug Discovery
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• Target validation
with a genetic and
pharmacological
approach
• Biomarker expression
and post-translational
modifications
• Cellular processes
• Assay development
and screening
• HTS
• vHTS
• Fragment-based
drug design
• Structure- and ligand-
based drug design
• Biophysical methods
• Medicinal and synthetic chemistry
• Computer Aided Drug Design
• Primary and secondary assays
• Protein production
• Protein crystallography
• ADME/DMPK
• In vitro pharmacology
• In vivo pharmacology
• Selection of
a preclinical candidate
to initiate IND-enabling
studies
PRECLINICAL CANDIDATE
LEAD OPTIMIZATIONHIT TO LEADHIT IDENTIFICATIONTARGET VALIDATION
ARTIFICIAL INTELLIGENCE (AI)-ASSISTED DRUG DISCOVERY
EXTENSIVE DRUG DISCOVERY EXPERTISE IN VARIOUS THERAPEUTIC AREAS
• AI-assisted structure design
• Prediction of ADME properties
• AI-assisted vHTS• Prediction of
interactions/binding
sites MOA (AI tools)
CLIENT CORE EXPERTISE
SELVITA BIOLOGY SELVITA ADME/PK
SELVITA CADD & MEDCHEM
Building a best fit for the project
We offer individual stand-alone capabilities
or multidisciplinary packages across
chemistry and biology
to support diverse client needs.
Selvita offers flexible support exactly
where & when our customer projects
require it.
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We build an optimal fit between our client’s core expertise, Selvita capabilities and project’sstrategic goals
Flexible approach to multidisciplinary projects
Tight organization of scientific activities speeds the drug discovery process
Flexible fit for a partner’s changing needs
Good match between partner’s and Selvita’s core competences and strengths
Benefits for our partners:
Medicinal Chemistry support Hit confirmation Hit to Lead/
Lead Optimisation
Chemistry
ADME
CompChem
Chemistry
Biology ADME
CompChem
X-raycrystallography
ADME/DMPK
BiologyMedChem
In vivo models
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Robust drug design feedback loop
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CLOSELY
COOPERATING
EXPERTS
SYNTHESIS
ANALYSIS
BIOLOGICALEVALUATION
DATA SHARING
DATA
EVALUATION
COMPOUND
DESIGN
• Computer-aided drug design• Novel scaffolds, patent busting,
open FTO space• Strategy suited for project requirements
• Multistep synthesis of novel compounds, design and optimization
• Customized chemical libraries• Process optimization, parametrization
and scale-up
• Compound identity and purity
confirmation
• Water and residual solvents analysis
• Secure shared database
• Frequent face-to-face meetings
and reporting
• Challenging the hypotheses, evaluating current approach
• On-target in vitro potency and efficacy assessment
• Cell-based functional assays and proliferation studies
• ADME determination
• In vivo pharmacology
Validated hit compound
Preclinical candidate
Hit ID Hit to Lead
Data-Driven & Hypothesis-Driven Drug Discovery
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• Assay development• Screening library design• HTS/FBS/vHTS• Hit resynthesis & expansion
Hit identification & confirmation
• Computational chemistry/ Machine learning• Protein expression, production & crystallography • Biology• ADME• Medicinal chemistry
Structure/ligand-guided & rational drug design
AI enabled phenotypic screening
Leadoptimization
Addressing the challenges of Hit ID and Hit to Lead phases
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Assays developed
Screen run
Hits confirmed
Chemical routes scouted
Preliminary IP assessment made
Clinical tractability assessed
SAR established
LEAD COMPOUND
Our impact in Lead to Candidate
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CANDIDATE DRUG DELIVERED
Selectivity optimized
Potency optimized
ADME liabilities addressed
Mechanism of action elucidated
PK-PD profiles optimized
Pharmacokinetics optimized
IP secured
Formulations scouted
Route developed
Safety studies run
Our Drug Discovery Philosophy
Be fast & efficient
Be smart: make good use of diverse information
to support drug design
Holistically embrace target-based and phenotypic
approaches
Do not over-simplify: use adequately sophisticated
pharmacological models and high content screening
methods
Create an environment for innovation
Flexible and dynamic team structure
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COMPUTATIONAL CHEMIST
BIOLOGY TEAMLEADER
Senior Scientist
PROJECT MANAGERMedicinal Chemistry Leader
CHEMISTRY TEAM LEADER
Senior Scientist
BIOCHEMISTRY SUPPORT
SCREENING/PROFILING SUPPORT
ADME/PK SUPPORT
CHEMISTRY TEAM
Communication and reporting
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Daily communication as-needed
Weekly project reports typically as a PowerPoint presentation
Weekly or biweekly teleconferences between Project Manager and the Client
Face-to-face meetings as required
In order to facilitate more efficient project communication, we encourage direct scientist to scientist contact, simultaneously to discussions with the Project Leader.
Project Leader
Research Group
Selvita Database
CLIENT
Project Leader
Research Group
Partner DatabaseELN or securedata exchange
Broad and deep experience delivering advanced assets
PROJECTSHIT IDENTIFICATION
HIT TO LEAD
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LEADOPTIMIZATION
CANDIDATESELECTION
PHASE I
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10
6
2
1
1
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THERAPEUTIC AREA
ONCOLOGY
NEUROSCIENCES
RESPIRATORY
INFLAMMATION
METABOLIC DISEASE
DERMATOLOGY
OPTHALMOLOGY
ANTI-INFECTIVES
OTHER / RARE DISEASES
Experienced drug discovery team
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Over 150 years of combined experience in oncology, CNS, inflammation, metabolic diseases, anti-infectives,
neuroinflammation, pain, antibacterial, fungicides, respiratory, innate immunity
Thorough experience in kinases, GPCRs, proteinases, enzymes, transcription regulators, macromolecular interactions,
PROTACs
Tom Coulter
Integrated Drug Discovery Director
Wojciech Czardybon
Drug Discovery Consulting Director,
MedChem
Davide Franceschini
Drug Discovery, Biology
Przemyslaw Zawadzki
Director of Medicinal Chemistry
AnnaKarawajczyk
Head of Computational
Chemistry
Piotr Graczyk
Consulting Director
Chemistry
Cyprian Cukier
Head of Protein Crystallography
Laboratory
Jan Smagur
Cell and Molecular Biology Director
BoguslawLupa
Biochemistry Department
Director
SCIENTIFIC CAPABILITIES
Computational Support – main activities
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• Homology modeling
• Druggability analysis
• Analysis of the binding pocket
• Analysis of a family of the target protein
• Prediction of structural consequences upon a point
mutation
Target preparation and holistic analysis
• Computational chemistry/ Machine learning
• 3D pharmacophore or/and shape screening: classical and
with
AI implementation
• 2D pharmacophore/fingerprint/ substructure screening
• Docking
Ligand-based and structure-based virtual screeningTARGET PREPARATION
AND HOLISTIC ANALYSISLIGAND-BASED
AND STRUCTURE-BASED VIRTUAL SCREENING
Computational Support
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• Prediction of properties, their analysis and structure filtration
according to the need of the project
• Virtual library design meeting requirements of the project
• Triage
• Library enumeration and processing with incorporated synthetic
feasibility
• Application of structural filters to remove undesired groups
and toxicophores
• Molecular descriptor calculations used for SAR analysis
and compounds quality assurance
• Similarity and diversity analysis
• Identification of IP space
• AI based models for analysis and classification
of compounds according to the scope of the project
CheminformaticsCHEMINFORMATICS
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Screening assays & compound profiling
• Medium/high throughput mode
• 96/384/1536-well plate formats
• Recombinant cell lines (more than 200 cell lines)
• Various read-outs:
• End-point and continuous enzymatic assays
• Luminescence, Abs, FI, FP, FRET, TR-FRET, Alpha Technology
• Biochemical activity and biophysical binding assays
• Compound profiling (MoA, competitiveness etc.)
• Compound libraries screening in HTS mode
• In-house Compound Collection:
• Diverse compounds (160K cmpds)
• Fragments (1.5K)
• Focused custom libraries
Variable assay formats & detection modes• VARIABLE ASSAY FORMATS & DETECTION MODES
Medicinal Chemistry
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• 150 Chemists
• 50% PhDs
• 11 different nationalities
• 21% foreigners
• On average 8 years
industrial experience
• Stable organic growth
~20% y/y
• Oncology
• CNS
• Inflammation
• Respiratory
• Metabolic disease
• Anti-infectives
• One stop shop
strategy
• One location for all
IDD departments
• ELN implemented
• Strong IP and data
protection
• 11 fully equipped
chemistry modules
(~100m2 each)
• Capabilities for scale-up
up to 1kg
• Purification department
(including SFC)
• Analytical department
(LC-MS, SFC, NMR on-site)
• Over 50 satisfied partners
in 2019
• 95% collaborations based
on FTE model
• Several multiproject
collaborations
• Global presence –
US, Europe, Japan
RESOURCES OPERATIONS EQUIPMENTTHERAPEUTIC AREAS PARTNERSHIP
In vitro biochemical, biophysical
and cell-based assays
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Expertise with various classes of:
• enzymes e.g. as kinases, phosphatases, metabolic
enzymes, immuno-modulatory enzymes
• protein receptors e.g. GPCRs, nuclear receptors
Biochemical activity assays: end-point and continuous,
coupled
Biophysical binding assays: radioligand-based,
FTS, SPR, ITC, FP, MST
Functional cell-based assays:
• analysis of phosphorylation and de-
phosphorylation
• analysis of signal transduction
• protein biomarkers (Western Blot or ELISA assays)
Implementation
of multiple
biochemical,
biophysical
and cell-based
assays
to facilitate target
ID, validation
and in vitro
efficacy
assessment
Structural biology
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• Comprehensive gene-to-structure service
• Crystallization-grade proteins (E. coli, insect and
mammalian expression systems)
• Automated screening of up to 1200 crystallization
conditions using Crystal Gryphon, Art Robbins
Instruments)
• Monitoring of crystal growth using UV fluorescence
microscope (UVEX-p plate-scanning microscope, JANSi)
• Extensive crystal optimization (grid screening,
temperature, seeding etc.)
• Protein-ligand crystals via soaking or co-crystallization
• Diffraction measurements at synchrotron facilities in
Europe
• Structure determination using Molecular Replacement
and experimental phasing
• HIT VALIDATION / HIT-TO-LEAD DEVELOPMENT / LEAD OPTIMIZATION
ADME Capabilities
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PHYSICO-CHEMICAL PROFILING
• Kinetic Solubility• Thermodynamic
Solubility• Lipophilicity (LogD/LogP)• pKa determination
IN VITRO PERMEABILITY STUDIES
• Passive Transport Assessment• PAMPA GI, BBB
• Active Transport Assessment• Caco-2 Permeability• MDR1-MDCKII Permeability
IN VITRO METABOLISM STUDIES
• Microsomal stability• S9 Stability• Hepatocyte Stability• Plasma Stability• Metabolite Profiling and
Identification
IN VITRO BINDING STUDIES
• Plasma Protein Binding – Rapid Equilibrium Dialysis
• Plasma Protein Binding – High Sensitivity Binding Kit
• Tissue Binding – Rapid Equilibrium Dialysis
CYP STUDIES
• Inhibition of the cytochrome P450 isoform activity (IC50, screening assay)
Q-Exactive Plus Q-FT-HR-MS/MS (Thermo Fisher Scientific)
Sirius T3 (PION)
Bioanalytical Capabilities
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• Method Development/Transfer
• Method Verification
• Method Validation
• Qualitative Analysis
• Quantitative Analysis
Matrices: Plasma and Tissue Homogenates
State-of-the-art highly sensitive instrumentation
• Altis ESI/APCI TSQ (Thermo Fisher Scientific)
• Q-Exactive Plus Q-FT-HR-MS/MS (Thermo Fisher Scientific)
• LCMS-8050, ESI/APCI-QQQ (Shimadzu)
• LCMS-6470 ESI/APCI-QQQ (Agilent)
• AmaZon SL, ESI/APCI-IT (Bruker)
• AmaZon Speed ESI/APCI-IT (Bruker)
• Sirius T3 (PION)GMP/GLP compliant facility
In vivo preclinical pharmacology
PARTNERSTUDY TYPE SELVITA
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• DESIGN• COORDINATION
• MODEL SELECTION
• IN VIVO EXPERIMENT
• GENERAL ROUTINE ANALYSIS
IN VIVO PHASE WITHSPECIALIZED PRIVATE OR ACADEMIC INSTITUTIONS
Disease expertise: • CNS
(e.g. psychiatric diseases, neurodegeneration)
• Cancer(e.g. xeno and allo-grafts)
STUDY TYPE MOUSE RAT
Pharmacokinetic
Pharmacodynamic
• CUSTOMIZED ANALYSIS WITH PECULIAR TOOLS
• CONCLUSION• REPORTING
• DATA ANALYSIS
• DISCUSSION AND REPORTING
SELVITA
OUR TEAM SUCCESSFULLY DESIGNS, COORDINATES
AND ANALYZES DATA FROM STUDIES
PERFORMED IN ANIMALS
PK
PD
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SelvitaKrakow
/Biotechnology-Company/Selvita-SA
THANK YOU FOR ATTENTION!
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SelvitaKrakow
/Biotechnology-Company/Selvita-SA
Get in touch with us: [email protected]