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Structure-based Drug Design

Pain relievers: aspirin:

Pain relievers: aspirin Analgesic (pain reliever) Antipyritic (fever reducer) Anti-inflammatory Anticoagulent Inhibits production of prostaglandins (pain messengers) History of Aspirin Hippocratus: powder made from the bark and leaves of the willow tree to help heal headaches, pains and fevers Henri Leroux & Raffaele Piria: purification of active ingradient from the plant 1899 Hoffman: formulation and patent

Antibacterial drugs: penicillins:

Antibacterial drugs: penicillins 1941 Prevents crosslinking between proteins and therefore cell wall synthesis (mucoproteins).

Aspirin substitutes:

Aspirin substitutes Now banned Tylenol Advil Aleve Orudis KT



Antibacterial drugs: sulfa drugs:

Antibacterial drugs: sulfa drugs Chemical mimic-type poison for bacteria 1935

Other antibacterial drugs:

Other antibacterial drugs Fluoroquinolone bind to bacterial ribosomes inhibits bacterial DNA replication

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Structure-based Drug Design Cycle Target identification and validation Assay development Virtual screening (VS) High throughput screening (HTS) Quantitative structure – activity relationship (QSAR) and refinement of compounds Characterization of prospective drugs Testing on animals for activity and side effects Clinical trials FDA approval

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Drugs derived from structure-based approaches Nelfinavir in the active site of HIV-1 protease: Agouron's AIDS drug nelfinavir (brand name Viracept) is one of the drugs on the market that can be traced directly to structure-based methods.

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Capoten Captopril ACE Hypertension 1981 Bristol-Myers Squibb Trusopt Dorzolamide Carbonic anhydrase Glaucoma 1995 Merck Viracept Nelfinavir HIV protease HIV/ AIDS 1999 Agouron (Pfizer) and Lilly Tamiflu Oseltamivir Neuraminidase Influenza 1999 Gilead and Roche Gleevec Imatinib BCR- Abl Chronic myelogenous leukaemia 2001 Novartis Drugs derived from structure-based approaches

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Determination of Target Structure Crystal structure of Rhodopsin: A G protein-coupled receptor. Palczewski et al . Science (2000) 289 , 739- 45.

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A. Binding site comprising three binding pockets B. Crystallographic screening locates molecular fragments that bind to one, two or all three pockets C. A lead compound is designed by organizing all three fragments around a core template D. Growing out of a single fragment

Example Combinatorial Library:

Example Combinatorial Library NH R1 R2 R3 Scaffold “R”-groups R1 = OH OCH 3 NH 2 Cl COOH R2 = phenyl OH NH 2 Br F CN R3 = CF 3 NO 2 OCH 3 OH phenoxy Examples NH OH CN OH NH OH O CH 3 NH C OH OH O CF 3 NH C OH OH O O For this small library, the number of possible compounds is 5 x 6 x 5 = 150

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Lead Identification by Fragment Evolution

Similarity Paradox:

Similarity Paradox

Descriptors of Molecular Structure & Properties:

Descriptors of Molecular Structure & Properties 1D-descriptors encode chemical composition & physicochemical properties MW, C m O n H k ,hydrophobicity 2D-descriptors encode chemical topology Connectivity indices, degree of branching, degree of flexibility, # of aromatic bonds 3D-descriptors encode 3D shape, volume, functionality, surface area Pharmacophore – the spatial arrangement of chemical groups that determines its activity

Lipinski Rule of Five (1997):

Lipinski Rule of Five (1997) Poor absorption and permeation are more likely to occur when there are more than 5 hydrogen-bond donors, more than 10 hydrogen-bond acceptors, the molecular mass is greater than 500, or the log P value is greater than 5. Further research studied a broader range of physicochemical and structural properties Related problems: Compound toxicity Compound mutagenicity Blood-brain barrier penetration Central nervous system activity

In Silico ADME Models:

In Silico ADME Models Computational methods can predict compound properties important to ADME, e.g. LogP, a liphophilicity measure Solubility Permeability Cytochrome p450 metabolism Means estimates can be made for millions of compouds, helping reduce “attrition” – the failure rate of compounds in late stage

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Structure of Cytochrome P450: responsible for primary metabolism of majority of drugs in human body -likely to herald a new era of structure-based design in the modulation of metabolic properties of drugs. Can metabolism properties be modulated?

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