Drug Design Lecture1

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

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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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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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Plant Origin

Microbiological Origin


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High Through Output Screening (HTS)

Side Effects Screening (Pharmacovigilance)

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Serendipity

Clonidine

Sildenafil

Minoxidil

Natural Neurotransmitter

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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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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

Documents

Drug Design Lecture1