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7/25/2019 Drug Design Lecture1
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Mahmoud Salama , PhD
Faculty of Pharmacy
Department of Pharmaceutical ChemistryEmail: [email protected]
Drug Design
Lecture I
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20
th
Century: Antibiotic Era
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20
th
Century: NSAIDS
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Research and Development Phases
The whole process takes 10 -1 5 yearsCost = $ 1.3 billion
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Research and Development Phases
The ideal drug candidates should be:
1- Potent2- Selective3- Physical and Metabolic stable4- Non-mutagenic5- Non- teratogenic6- Non- Toxic
7- Patentable8- Manufacturable
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Two Billion Dollar Lesson
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Two Billion Dollar Lesson
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Two Billion Dollar Lesson
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Drug: A chemical compound with specific pharmacological activityand minimal toxicity.
Effective Less toxic
Highly selective
Molecular Target: A target responsible for executing the biologicalfunctions and in case of dysfunction, this will lead to evolution of
clinical problems.
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Important Definitions
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Receptor: A protein molecule embedded within the surface of thecellular plasma membrane receiving signals from outside the cell.
Hit: A selected series of active compounds either synthesized or
naturally occurred.
Hit To Lead: Development / Optimization of the hit compoundstowards generation of the most active prominent candidate.
Lead: An active prominent compound to enroll clinical trials.
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Important Definitions
Biological B
Natural Product N
Semi-synthetic modification to
Natural Product ND
Totally Synthetic S
Totally Synthetic but with
natural product
pharmacophore S*
Natural Mimic NM
Vaccines V
B
15%N
4%
ND
22%S
29%
S*
4%
NM
20%
All New Chemical Entities 1981-2010
V
6%
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Drug Receptor Interaction
Molecular Recognition:
Recognition of the biological molecular target andinteracting with ligands (potential drug candidates),
then visualization in three dimensional model.
KEY LOCK MODEL INDUCED FIT MODEL
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Natural Products Screening
High Through output Screening
Side Effects Screening (Pharmacovigilance)
Serendipity
Natural Neurotransmitters
Computer Aided Drug Design
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1 Finding Lead Compounds
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Natural Materials Screening
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Finding Lead Compounds
Plant Origin
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Natural Materials Screening
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Finding Lead Compounds
Plant Origin
Microbiological Origin
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High Through Output Screening (HTS)
Side Effects Screening (Pharmacovigilance)
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Finding Lead Compounds
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Serendipity
Clonidine
Sildenafil
Minoxidil
Natural Neurotransmitter
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Finding Lead Compounds
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Computer Aided Drug Design
Rational Drug Design via identifying molecular target
Design of active hits based on pharmacophore
Pharmacophore: Chemical segment of the molecule which isessential for binding with the receptor to produce Pharmacologicalactivity
Optimization of Hit to lead compound
Prediction of binding affinity of ligands to the molecular target priorsynthesis
Advantages??
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Finding Lead Compounds
Disadvantages??
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2 Pharmacophore Identification
Pharmacophore: Chemical segment of the molecule which is essential forbinding with the receptor to produce Pharmacological activity
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3 Hit Design
The design is followed by biological and pharmacological evaluation.
High Through Output Screening: An automated method for screening alibrary of compounds (10,000 up to 2 million compounds) biologically forgeneration of Hit compounds.
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4 Hit to Lead Generation
Not all Hit compounds are eligible to be drug candidates.
Hit to Lead generation elucidates the structural activity relationship (SAR)for further optimization.
Tyrosine Kinase Inhibitor Used for treatment of Leukemia SAR elucidates the importance of
substituents in the meta position for activity
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4 Hit to Lead Generation
The biological data derived for the synthesized hits will help to elucidatemathematical model correlating between the activity and chemical
properties (descriptors)
Based on this mathematical model, the activity for virtual library can bepredicted prior to its synthesis, this approach is called QuantitativeStructural Activity Relationship (QSAR)
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4 Lead Optimization
A library of lead compounds is generated synthetically to be biologicallyevaluated for optimization and generation the most active drug candidate
prior to the clinical trials.
Newly approved FDA Tyrosine Kinase Inhibitor Used for treatment of Chronic Mylogenious Leukemia Newly available in the market
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Challenges related to drug discovery