Drug Discovery Primary objective－ design & discovery of new compounds that are suitable for use as drugs A team of workers－ chemistry, biology, biochemistry, pharmacology, mathematics, medicine & computing … Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Administration method Development of tests Requirements Synthesis of the drug Administration method Development of tests Procedures to establish how it operates in the body (v) safety assessment research into the biological and chemical nature of diseased state. Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Potency: quantitative nature of the effect Drugs: Definition Chemical substances that are used to prevent or cure diseases in humans, animals and plants Activity: Pharmaceutical/pharmacological effect on the subject, e.g. Analgesic or β-blocker Potency: quantitative nature of the effect An analgesic, or painkiller, is any member of the group of drugs used to achieve analgesia — relief from pain. The word analgesic derives from Greek ἀν-, "without", and ἄλγος, "pain".[1] used for the management of cardiac arrhythmias, protecting the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention),[1] and, in certain cases,hypertension.[2][

Drugs Properties: ADMET Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Areas Influencing DD Molecular Biology on Drug Discovery High-Throughput Screening Combinatorial Chemistry Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Molecular Biology Influence Genetic information Biochemical and chemical terms. Cloning and expressing genes that encode therapeutically useful protein Having or exhibiting healing powers: a therapeutic agent; therapeutic exercises.  Of or relating to the medical treatment of a disease or condition.

High Throughput Screening Widely used in the pharmaceutical industry. Automation to quickly assay the biological or biochemical activity of a large number of drug-like compounds.

Combinatorial Chemistry Laboratory technique in which millions of molecular constructions can be synthesized and tested for biological activity.

Even the drugs abused have their activity. No drug is completely safe. Drug: agent used for the psychotic effect by the media or general public. Even the drugs abused have their activity. No drug is completely safe. Suitable quantity to cure or excess to be poisonous! e.g. aspirin, paracetamol can be toxic if excesses. Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Pharmacogenetics It is the branch of pharmacology concerned with the effect of genetic factors on reactions to drugs. how people respond to medicines Correlating heritable genetic variation to drug response Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Pharmacogenetics Biotechnological science combines techniques of medicine pharmacology (iii) genomics developing drug therapies to compensate for genetic differences in patients which cause varied responses to a single therapeutic regimen. Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Pharmacogenomics How genes affect persons response to drugs. Pharmacology (science of drugs) Genomics (the study of genes and their functions) Develop effective, safe medications & doses tailored to a person’s genetic makeup. Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Single Nucleotide Polymorphisms Most common type of genetic variation among people. Each SNP represents a difference in a single DNA building block, i.e. nucleotide.

Single Nucleotide Polymorphism AAGCCTA AAGCTTA contain a difference in a single nucleotide.

In reality few SNPs act on their own Genome-Wide Association Studies identify groups of SNPs linked to a certain condition Non-coding regions of DNA When frequent enough in a population they can be linked to specific traits, e.g. a disease SNP microarrays can be used to probe hundreds of thousands of SNPs in parallel

Methods of DD Past: (i) Identification of active ingredient from traditional remedies (2) serendipitous discovery. Current: Diseases are controlled at molecular & physiological level. Information of Human Genome Physiology (/ˌfɪziˈɒlədʒi/; from Ancient Greek φύσις (physis), meaning "nature, origin", and -λογία (-logia), meaning "study of"[1]) is the scientific study of normal function in living systems.[2] A sub-discipline of biology, its focus is in how organisms, organ systems,organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system.[3] Given the size of the field it is divided into, among others, animal physiology (including that of human), plant physiology, cellular physiology

Drug Discovery - Methods Pre 1919 Herbal Drugs Serendiptious discoveries 1920s, 30s Vitamins Vaccines 1940s Antibiotic Era R&D Boost due to WW2 1950s New technology, Discovery of DNA 1960s Breakthrough in Etiology 1970s Rise of Biotechnology Use of IT 1980s Commercialization of Drug Discovery Combinatorial Chemistry 1990s Robotics Automation Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Drug Discovery - Methods Random Screening Molecular Manipulation Molecular Designing Drug Metabolites Serendipity Change Management http://www.ahrq.gov/professionals/education/curriculum-tools/teamstepps/longtermcare/module8/igltcchangemgmt.pptx

Drug Discovery – Pipeline Target Identification Target Validation Lead Identification Lead Optimization Pre-Clinical Pharmacology & Toxicology

Drug Discovery Animal Studies Clinical Tests Commercialization Gene or Genome Sequencing Target Validation Discovery Lead Pre- Clinical Manufac -turing Phase I Phase II Phase III Distribution Drug Discovery Animal Studies Clinical Tests Commercialization

Synthetic DNA as Drugs

Why Can DNA Be Used as Drugs? The Structure of DNA and RNA Four bases in DNA and RNA They are A, T (U in RNA), G and C Genetic information is stored in the sequence of A, T, G, C in DNA DNA double stranded RNA double/single stranded A pairs to T (U in RNA) only and G pairs to C only DNA-DNA, RNA-RNA, DNA-RNA

Why Can DNA Be Used as Drugs? The Base Pairs DNA-DNA: A-T, G-C RNA-RNA: A-U, G-C DNA-RNA: A-U, G-C

Why Can DNA Be Used as Drugs? The Central Dogma of Molecular Biology DNA: double stranded, contains genetic information RNA: single stranded Protein: the function molecule of life, function determined by the sequence of amino acids

Why Can DNA Be Used as Drugs. How People Get Disease Why Can DNA Be Used as Drugs? How People Get Disease? Mono-genetic disorder Currently, a total of ~4,000 genetic disorders are known Some are single genetic disorder Changes (mutations) of the sequence of one gene (DNA) Point mutation Deletion And more List of genetic disorders at http://en.wikipedia.org/wiki/List_of_genetic_disorders The mutated genes produce proteins that cannot function properly, diseases occur Examples: Sickle-cell anemia, Cystic fibrosis (1/3900, most common, difficult breathing, die in 20s-30s, no cure), Color blindness

Why Can DNA Be Used as Drugs. How People Get Disease Why Can DNA Be Used as Drugs? How People Get Disease? Poly-genetic disorder Mutations occur in many genes Do not have a clear cut of inheritance But do “run in families” The mutated genes produce proteins that cannot function properly, diseases occur Difficult (not impossible) to study and treat because direct cause is unknown Examples: Heart disease, hypertension, diabetes, obesity, cancers, low IQ

Why Can DNA Be Used as Drugs. How People Get Disease Why Can DNA Be Used as Drugs? How People Get Disease? Bacteria and virus infections Smallpox 300-500 million deaths in 20th century Eliminated by vaccination HIV/AIDS Human immunodeficiency virus/acquire immunodeficiency syndrome Still taking many lives each year, in 2000, 2.8 million Hepatitis B 0.1 million lives taken in 2000 Liver inflammation, vomiting, and rarely death, but can lead to cancer Tuberculosis Bacteria, mostly infect lung, but also other parts of body In 2004, 1.7 million deaths

Why Can DNA Be Used as Drugs Why Can DNA Be Used as Drugs? How to stop genetic disorder using DNA drugs? Design a short DNA sequence that matches the sequence of mRNA that is transcribed from the mutated gene (which causes diseases) The DNA drug binds to the mRNA (A-U, G-C) The mRNA cannot be translated to protein Because no disease-causing protein, disease is cured

Design DNAs that can stop the critical gene expressions Why Can DNA Be Used as Drugs? How to stop diseases caused by microorganisms using DNA drugs? Select one or more genes that are critical for the disease-causing bacteria or virus Design DNAs that can stop the critical gene expressions The bacteria or virus dies and diseases cured

Why Use Synthetic DNA? Natural DNA will be digested by enzymes, and also can cause immune response Synthetic DNA cannot be recognized by enzymes, so they are stable and may not cause immune response So, synthetic DNA can selectively block gene expression