Principles of Drug Design


Presentation Description

All chemical molecules are not drugs


Presentation Transcript

Slide 1: 


Slide 2: 

PRINCIPLES OF DRUG DESIGN Mr. SRINIVAS NANDYALA II/II M. Pharm. A.K.R.G. College of Pharmacy Nallajerla, W. G. Dist, AP.

What is a drug? : 

What is a drug? Defined composition with a pharmacological effect Regulated by the Food and Drug Administration (FDA) What is the process of Drug Discovery and Development?

Drugs : 

Drugs Small Molecules Natural products fermentation broths plant extracts animal fluids (e.g., snake venoms) Synthetic Medicinal Chemicals Project medicinal chemistry derived Combinatorial chemistry derived

Slide 5: 

Biologicals -Natural products (isolation) -Recombinant products -Novel recombinant products Drugs

Discovery vs. Development : 

Discovery vs. Development Discovery includes: Concept, mechanism, assay, screening, hit identification, lead demonstration, lead optimization Discovery also includes In Vivo proof of concept in animals and concomitant demonstration of a therapeutic index Development begins when the decision is made to put a molecule into phase I clinical trials

Discovery and Development : 

Discovery and Development The time from conception to approval of a new drug is typically 10-15 years The vast majority of molecules fail along the way The estimated cost to bring to market a successful drug is now $800 million!! (Dimasi, 2000)

Drug Discovery Processes Today : 

Drug Discovery Processes Today Molecular Biological Hypothesis (Genomics) Chemical Hypothesis Physiological Hypothesis Primary Assays Biochemical Cellular Pharmacological Physiological Sources of Molecules Natural Products Synthetic Chemicals Combichem Biologicals + Initial Hit Compounds Screening

Drug Discovery Processes - II : 

Drug Discovery Processes - II Initial Hit Compounds Secondary Evaluation - Mechanism Of Action - Dose Response Initial Synthetic Evaluation - analytics - first analogs Hit to Lead Chemistry - physical properties -in vitro metabolism First In Vivo Tests - PK, efficacy, toxicity

Drug Discovery Processes - III : 

Drug Discovery Processes - III Lead Optimization Potency Selectivity Physical Properties PK Metabolism Oral Bioavailability Synthetic Ease Scalability Pharmacology Multiple In Vivo Models Chronic Dosing Preliminary Tox Development Candidate (and Backups)

Drug Discovery & Development : 

Drug Discovery & Development Identify disease Isolate protein involved in disease (2-5 years) Find a drug effective against disease protein (2-5 years) Preclinical testing (1-3 years) Formulation Human clinical trials (2-10 years) Scale-up FDA approval (2-3 years) File IND File NDA

Technology is impacting this process : 

Technology is impacting this process Identify disease Isolate protein Find drug Preclinical testing GENOMICS, PROTEOMICS & BIOPHARM. HIGH THROUGHPUT SCREENING MOLECULAR MODELING VIRTUAL SCREENING COMBINATORIAL CHEMISTRY IN VITRO & IN SILICO ADME MODELS Potentially producing many more targets and “personalized” targets Screening up to 100,000 compounds a day for activity against a target protein Using a computer to predict activity Rapidly producing vast numbers of compounds Computer graphics & models help improve activity Tissue and computer models begin to replace animal testing

Slide 13: 

Biological Discovery High Volume Screening Combinatorial Diversity Rational [Structure, Design, Informatics] Lead Series Biodisposition Toxicity Efficacy Pharmacokinetics IND Lead Discovery Iterative Preclinical Research Process R&D Principles of Drug Design Full Toolbox Required for Success!

Slide 14: 

Principles of Drug Design Lipinski’s Rule of Fives MW < 500 Fewer than five H-bond donating functions Fewer than 10 H-bond accepting functions Calculated logP (ClogP) between –1 and +5 H2O n-octanol P = [D]Lipid [D]Water log P

Slide 15: 

Lipinski’s Rule of Fives …. Examples Principles of Drug Design MW = 180 Da # H-bond donors = 1 # H-bond acceptors = 4 ClogP =2.44 MW = 282 Da # H-bond donors = 0 # H-bond acceptors = 5 ClogP =4.15 Aspirin Artemisinin

Slide 16: 

Lipinski’s Rule of Fives …. Examples Principles of Drug Design MW = 429 Da # H-bond donors = 1 # H-bond acceptors = 3 ClogP = 4.74 MW = 407.5 Da # H-bond donors = 3 # H-bond acceptors = 7 ClogP = -0.17 RU-486 Amlodipine

Slide 17: 

Pharmacophore ………an ensemble of steric and electronic features necessary to ensure the optimal supramolecular interactions with a specific biological target to trigger (or block) a biological response General Approaches Principles of Drug Design

Slide 18: 

Chemical and Biochemical Isosteres Principles of Drug Design Grimm’s Hydride Displacement Law Hinsberg’s Ring Equivalents Benzene, thiophene and pyridine are equivalent. e.g., H1-receptor antagonists … tripelennamine and methaphenilene

Slide 19: 

Chemical and Biochemical Isosteres Principles of Drug Design Friedman’s Bioisosteres …. chemical and physical properties Uracil ….. Fluorouracil (antineoplastic) Salicylic acid ….. Salicamide (analgesic) Estradiol ….. Diethyl stilbestrol (estrogenic)

Slide 20: 

Lengthening Alkyl Chains Principles of Drug Design Increase hydrophobicity, decrease water solubility Increase conformational flexibility May be directly involved in interaction with receptor Morphine

Slide 21: 

Flexibility of Drugs and Affinity Principles of Drug Design DGOBS = DGComplex + DGSolv + DGConf = -RT ln K

Slide 22: 

Dopamine Receptor Agonist Principles of Drug Design II < III < IV < I

Drug Discovery Program Rationales : 

Drug Discovery Program Rationales Unmet Medical Need Me Too! - Market - ($$$s) Drugs in search of indications Side-effects often lead to new indications Indications in search of drugs Mechanism based, hypothesis driven, reductionism

Serendipity and Drug Discovery : 

Serendipity and Drug Discovery Often molecules are discovered/synthesized for one indication and then turn out to be useful for others Tamoxifen (birth control and cancer) Viagra (hypertension and erectile dysfunction) Salvarsan (Sleeping sickness and syphilis) Interferon-a (hairy cell leukemia and Hepatitis C)

Issues in Drug Discovery : 

Issues in Drug Discovery Hits and Leads - Is it a “Druggable” target? Resistance Pharmacodynamics Delivery - oral and otherwise Metabolism Solubility, toxicity Patentability

A Little History of Computer Aided Drug Design : 

A Little History of Computer Aided Drug Design 1960’s - Viz - review the target - drug interaction 1980’s- Automation - high trhoughput target/drug selection 1980’s- Databases (information technology) - combinatorial libraries 1980’s- Fast computers - docking 1990’s- Fast computers - genome assembly - genomic based target selection 2000’s- Vast information handling - pharmacogenomics

Acknowledgements : 

Acknowledgements Chairman of A.K.R.G. Educational Institutes. Prof. G. Vijaya kumar. Prof. Shakthi prasanna sahoo. Mr. M srinivasarao and Kishore kumar. Mr. Arun kumar raju and Narendra raju. Friends and Classmates.

References : 

References Vogale’s Drug discovery and Evaluation Screening methods in Pharmacology by “N S parmar” Foye’s Medicinal chemistry Medicinal chemistry by “S N Pandeya” Mendely Academic research papers.

Slide 29: