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Drug design

https://www.yourgenome.org/facts/how-are-drugs-designed-and-developed 2
Stage1:
Drug Discovery
 Drug sources:
 Natural:
 e.g.: Insulin (Cow's pancreas)
 Morphine (Opium)
 Traditional Medicine Texts
 Identification of chemical structure :
 NMR
 UV
 IR
 HPLS
 Chromatography
 Mass spectroscopy

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Stage1:
Drug Discovery
 Semi-synthetic & Synthetic:
 Penicillin Derivative :
 Amoxicillin - Ampicillin – Penicillin V
 Morphine Derivative:
 Buprenorphine
 Diphenoxylate
 Dextromethorphan

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Stage1
Drug Discovery
 Study
 Understanding the Disease
 Target selection
 Suitable cell line cultures
 Keep cells alive
 Weight and hydrophilic and lipophilic balance
 Screening
 2-5 years lasts

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Stage2
Preclinical Development
 Safety and toxicity
 In animal lab
 1.5 years

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Stage3
Clinical Development(5-7 years)
i. In 20-100 Healthy volunteer
i. Purpose: Safety and dosage - Pharmacokinetic
ii. In 100-200 patients
ii. Purpose: Does it work in patient?
i. In 1000-3000 patient
ii. Purpose
i. long-term
ii. rare side effects
iii. FDA approval
iv. Post marketing

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The Medicine Development Process
time & costs

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Computer drug design
■ save time and costs

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QSAR
■ Quantitative Structure Activity Relationship
– QSAR study was published by Hansch and his coworkers in 1962.

Quantitative Structure-Activity Relationships/ Department of Medicinai Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612 (U.S.A.) 10
 Activity
■ Bioavailability
■ Toxicity
■ IC50
– This quantitative measure indicates how much of a particular drug or other
substance (inhibitor) is needed to inhibit a given biological process (or component
of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.
■ LD50
■ ….

 Quantitative structure–activity relationships (QSARs) to estimate ionic liquids ecotoxicity EC50 (Vibrio fischeri) P. Luis ⁎, A. Garea, A. Irabien
 Quantitative structure-activity relationship (QSAR) studies in genetic toxicology: mathematical models and the "biological activity" term of the relationship/Romualdo Benigni,Alessandro Giuliani
 QSAR Model for Drug Human Oral Bioavailability/Fumitaka Yoshida,and John G. Topliss 11
Importance of QSAR?
■ Developing new drugs is a very expensive and time consuming process
■ Accelerate drug discovery
– Try and error
■ Lipinski’s rule of five(1997)
– No more than 5 hydrogen bond donors
– No more than 10 hydrogen bond acceptors
– A molecular mass less than 500 daltons
– An octanol-water partition coefficient log P not greater than 5

Drug discovery beyond the rule-of-five/Ming-Qiang Zhang and Barrie Wilkinson 12

Data collection
■ Target
■ AT LEAST 30-40 Component
■ Homolog Component

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Data collection
■ Journals
– Drug discovery today
– Journal of chemical information and modeling
– Journal of computer aided drug design
– Molecular informatics
– Journal of medicinal chemistry
– European Journal of medicinal chemistry
– Journal of Cheminformatics
– Journal of bioinformatics
– TMC Bioinformatics
– Medicinal Chemistry Research

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Structural design optimization

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Structural design optimization
■ HyperChem
■ Coussion
■ Espresso

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Data collection
■ Databases
– GDB Databases
– Pubchem
– Zinc
– Drug Bank
– Binding DB

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Data collection
■ QSARDB
■ QSARDB is a smart repository for (Q)SAR/QSPR models and datasets, ready for
discovery, exploring, citing and predicting.

http://qsardb.org/ 18
Molecular descriptor generation
■ DRAGON
■ Advanced Chemistry Development, inc (ACD/Labs)
■ Spartan
– Molecular weight
– Average molecular weight
– Q+
– Q-
– Total charge
– SE
– SV
– …

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Descriptor selection
■ Correlation
■ Stepwise
■ …

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Model descriptor and validation

■ MLR
■ ….

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references
■ QSAR modelling: A therapeutic patent review 2010- present/ Amit Kumar Halder,
Ana S. Moura & M. Natalia D. S. Cordeiro
■ Targeting the NF-kB/IkBacomplex via fragment-based E-Pharmacophore virtual
screening and binary QSAR modelsTarek Kanana,b, Duaa Kanana,b, Ismail Erolb,c,
Samira Yazdid,2,Matthias Steind,Serdar Durdagi
■ Bioinformatics approaches for new drug discovery: a review/Kullappan Malathi &
Sudha Ramaiah

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