Presentation is loading. Please wait.

Presentation is loading. Please wait.

Bioinformatics Applications

Published byἈρέθουσα Παπαϊωάννου Modified over 6 years ago

Similar presentations

Presentation on theme: "Bioinformatics Applications"— Presentation transcript:

1 Bioinformatics Applications
Drug Discovery Pharmacogenomics 11/12/2018 Chuck Staben

2 Pharmaceutical Industry
$100,000,000,000 worldwide yearly 78% prescription 20% over-the-counter 2% diagnostics R&D expenditure ??>10 billion 11/12/2018 Chuck Staben

3 Drug Discovery Compounds Targets Drug Candidates Target Candidates
Refine 11/12/2018 Chuck Staben

4 Drug Approval Discovery Genomics, BioInfo Pre-clinical Clinical Review
5 years Pre-clinical 1 year Clinical 6 years Review 2 years 11/12/2018 Chuck Staben

5 Drugs-Therapeutic Categories
Inflammatory/Immunological ($50B) Cardiovascular ($20B) Metabolic/endocrine ($15B) Anti-infectives ($20B) Oncology ($7B) Neurological Pain Viagra! 11/12/2018 Chuck Staben

6 Anti-infectives Target-driven Compound-driven
Anti-bacterial, for example Non-toxic to humans Target-driven Compound-driven 11/12/2018 Chuck Staben

7 Target Paradigm-Bioinformatics
Present in all target pathogens Expressed growing vs non-growing? Essential growth vs survival Absent in humans Not expressed in target tissue? Other Criteria? Target Validation 11/12/2018 Chuck Staben

8 Target Refinement Known drug target in this class?
Known structure in class? Develop assay/high throughput screen refine “differential” screens? Determine target properties structure, binding/catalytic properties STRUCTURE BASED DESIGN 11/12/2018 Chuck Staben

9 Oncogenic Target Normal vs transformed cells
process found in cancer, not normal rapid DNA replication, eg. process unique to normal, not cancer loss of differentiated characteristic receptor response, etc. 11/12/2018 Chuck Staben

10 Anti-inflammatory Sketch Pad -Class input 11/12/2018 Chuck Staben

11 Overexpression protection
Compound Paradigm HTS to find active compounds whole cell assays? Bioinformatics and genomics to find targets! refine targets/compounds Expression screening Overexpression protection 11/12/2018 Chuck Staben

12 Combinatorial Chemistry
“Arrayed” chemistries (~1992) parallel automated syntheses permuted chemical libraries Can be “biased” by lead compounds, selected chemistries Millions of compounds 11/12/2018 Chuck Staben

13 High Throughput Screens
100,000 assays/day per system Require microminiaturization Microfluidics Lab-on-a-chip 11/12/2018 Chuck Staben

14 HTS/Preclinical Issues
Pharmacokinetic issues bulk transport, uptake, efflux, metabolism Tissue specificity Genetic/environmental variability 11/12/2018 Chuck Staben

15 Clinical Trials MAJOR Expense Phase I: 50-100 subjects for toxicology
Phase II: patients for efficacy, dose, safety Phase III: patients for efficacy, safety MAJOR Expense 11/12/2018 Chuck Staben

16 Pharmacogenomics Pharmacogenomics is the science of understanding the correlation of an individual's genetic make-up to his or her response to drug treatment. Understanding the genetic cause of differences in response will be useful in stratifying patient populations for clinical trials, accelerating timelines and reducing costs during clinical development. 11/12/2018 Chuck Staben

17 FDA Gold Mine "Identifying metabolic differences in patient groups based on genetic polymorphisms, or on other readily identifiable factors such as age, race, and gender, could help guide the design of dosimetry studies for such populations groups. This kind of information also will provide improved dosing recommendations in product labeling, facilitating the safe and effective use of a drug by allowing prescribers to anticipate necessary dose adjustments. Indeed, in some cases, understanding how to adjust dose to avoid toxicity may allow the marketing of a drug that would have an unacceptable level of toxicity were its toxicity unpredictable and unpreventable." 11/12/2018 Chuck Staben

18 Side Effects 90% of drug candidates fail in pre-clinicals
90% of remainder fail in clinical-many due to side effects Estimates of NSAID ulcers more deaths/year than due to melanoma, cervical cancer combined! 11/12/2018 Chuck Staben

19 Pharmacogenomic Loci Metabolism Variation Drug Target Variants
Disease Pathway 11/12/2018 Chuck Staben

20 Metabolism Variants Cytochrome P450s CYP2D6, (~10% Caucasian)
3A4,2C19 N-acetyltransferases (NAT1, NAT2) 40-60%!, isoniazid toxicity 11/12/2018 Chuck Staben

21 CYP2D6 ~25% all drugs ~10 population Substrates Antidepressants*
Amitriptyline (Elavil) Doxepin (Adapin, Sinequan) Fluoxetine (Prozac) Paroxetine (Paxil) …. Antipsychotics Haloperidol (Haldol) ... Beta blockers Propranolol (Inderal)* Timolol (Blocadren) Narcotics Codeine, tramadol (Ultram) Inhibitors Antidepressants sertraline (Zoloft) Cimetidine (Tagamet) Fluphenazine (Prolixin) Antipsychotics Haloperidol Perphenazine ~25% all drugs ~10 population 11/12/2018 Chuck Staben

22 Target/ Disease Pathway Variation
5-HT2A Receptor [clozapine (antipsychotic)] 5-HTT (serotonin uptake) variant associated with anxiety need for/success with Prozac? Apo4E  risk, Alzheimers AND  effect ACE inhibitors CETP, LPL, -fibrinogen (cholesteryl ester transfer protein, lipoprotein lipase)  response to HMG-CoA inhibitors (parvastatin) AND  risk of atherosclerosis 11/12/2018 Chuck Staben

23 Pharmacogenomic Loci Medical Informatics?? Association Studies
100,000 SNP markers, 1000 individuals QTL traits! Other Strategies?? Medical Informatics?? 11/12/2018 Chuck Staben

24 Bioinformatics-Genomics Therapy Evaluation
Gene Expression correlate with clinical progress/toxicity transcriptome level proteome level 11/12/2018 Chuck Staben

25 Improved Drug Development Model
Costs Drugs $$ Drugs $$ Costs 11/12/2018 Chuck Staben

Download ppt "Bioinformatics Applications"

Similar presentations

Dr Claes Wilhelmsson Executive Director Research & Development Innovation and the life sciences.

Dr Claes Wilhelmsson Executive Director Research & Development Innovation and the life sciences.
The Drug Discovery Process

The Drug Discovery Process
Presentation for HL7 RCRIM and Clinical Genomics SIG HL7 Working Group Meeting San Diego, CA 21Jan2004.

Presentation for HL7 RCRIM and Clinical Genomics SIG HL7 Working Group Meeting San Diego, CA 21Jan2004.
Pharmacogenetics and the Management of Breast Cancer: Optimization of Tamoxifen Therapy Mark E. Sobel, M.D., Ph.D. Executive Officer American Society for.

Pharmacogenetics and the Management of Breast Cancer: Optimization of Tamoxifen Therapy Mark E. Sobel, M.D., Ph.D. Executive Officer American Society for.
Dr. Almut Nebel Dept. of Human Genetics University of the Witwatersrand Johannesburg South Africa Significance of SNPs for human disease.

Dr. Almut Nebel Dept. of Human Genetics University of the Witwatersrand Johannesburg South Africa Significance of SNPs for human disease.
S TRUCTURAL B IOINFORMATICS. A subset of Bioinformatics concerned with the of biological structures - proteins, DNA, RNA, ligands etc. It is the first.

S TRUCTURAL B IOINFORMATICS. A subset of Bioinformatics concerned with the of biological structures - proteins, DNA, RNA, ligands etc. It is the first.
Pharmacogenomics in Drug Development FDA Science Board April 9, 2003 Brian B. Spear, Ph.D. Director, Pharmacogenomics Abbott Laboratories.

Pharmacogenomics in Drug Development FDA Science Board April 9, 2003 Brian B. Spear, Ph.D. Director, Pharmacogenomics Abbott Laboratories.
Clinical Genotyping and Personalized Medicine Michael D. Kane, PhD (1) Associate Professor of Bioinformatics (2) University Faculty Scholar (3) Chair of.

Clinical Genotyping and Personalized Medicine Michael D. Kane, PhD (1) Associate Professor of Bioinformatics (2) University Faculty Scholar (3) Chair of.
Drug Discovery Process

Drug Discovery Process
Doug Brutlag 2011 Genomics, Bioinformatics & Medicine Drug Development

Doug Brutlag 2011 Genomics, Bioinformatics & Medicine Drug Development
Re-Examination of the Design of Early Clinical Trials for Molecularly Targeted Drugs Richard Simon, D.Sc. National Cancer Institute linus.nci.nih.gov/brb.

Re-Examination of the Design of Early Clinical Trials for Molecularly Targeted Drugs Richard Simon, D.Sc. National Cancer Institute linus.nci.nih.gov/brb.
DG-031-CV-301 Coronary Artery Disease and Leukotriene Gene Markers.

DG-031-CV-301 Coronary Artery Disease and Leukotriene Gene Markers.
Paola CASTAGNOLI Maria FOTI Microarrays. Applicazioni nella genomica funzionale e nel genotyping DIPARTIMENTO DI BIOTECNOLOGIE E BIOSCIENZE.

Paola CASTAGNOLI Maria FOTI Microarrays. Applicazioni nella genomica funzionale e nel genotyping DIPARTIMENTO DI BIOTECNOLOGIE E BIOSCIENZE.
University of Utah Department of Human Genetics Pharmacogenomics Louisa A. Stark, Ph.D. Director.

University of Utah Department of Human Genetics Pharmacogenomics Louisa A. Stark, Ph.D. Director.
Stages of drug development

Stages of drug development
Important Points in Drug Design based on Bioinformatics Tools History of Drug/Vaccine development –Plants or Natural Product Plant and Natural products.

Important Points in Drug Design based on Bioinformatics Tools History of Drug/Vaccine development –Plants or Natural Product Plant and Natural products.
Obtaining and Negotiatiing a Position in Industry/Biotech Roy G. Smith Ph.D. Director, Huffington Center on Aging Professor, Department of Molecular and.

Obtaining and Negotiatiing a Position in Industry/Biotech Roy G. Smith Ph.D. Director, Huffington Center on Aging Professor, Department of Molecular and.
Integrating Scientific Advances into Regulation: Pharmacogenomics and Pharmacogenetics Janet Woodcock, M.D. Director, Center for Drug Evaluation and Research.

Integrating Scientific Advances into Regulation: Pharmacogenomics and Pharmacogenetics Janet Woodcock, M.D. Director, Center for Drug Evaluation and Research.
The Need for Organ Site Specific Cancer Research John T Isaacs Chemical Therapeutic Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

The Need for Organ Site Specific Cancer Research John T Isaacs Chemical Therapeutic Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
Richard D. Hockett, Jr. M.D. Sr. Clinical Research Physician Group Leader, Genomic Medicine FDA Clinical Pharmacology Advisory Committee Integrating Pharmacogenomics.

Richard D. Hockett, Jr. M.D. Sr. Clinical Research Physician Group Leader, Genomic Medicine FDA Clinical Pharmacology Advisory Committee Integrating Pharmacogenomics.

Similar presentations

Ads by Google