Principles of Drug Design


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All chemical molecules are not drugs


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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

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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

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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!

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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

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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

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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

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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

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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

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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)

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

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

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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.

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