strut based drug design-1

8/3/2019 Strut Based Drug Design-1

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Structure-based Drug Design


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Pain relievers: aspirin

Analgesic (pain reliever)

Antipyritic (fever reducer)

Anti-inflammatory

Anticoagulent

Inhibits production ofprostaglandins (painmessengers)

History of Aspirin

- Hippocratus: powder made from the

bark and leaves of the willow tree tohelp heal headaches, pains and fevers

- Henri Leroux & Raffaele Piria:

purification of active ingradient from

the plant

- 1899 Hoffman: formulation and patent


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Antibacterial drugs: penicillins

1941Prevents crosslinking between proteins

and therefore cell wall synthesis (mucoproteins).


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Aspirin substitutesNow banned Tylenol

Advil Aleve Orudis KT


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Antihistamines


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Antibacterial drugs: sulfa drugs

Chemical mimic-type poison for bacteria

1935


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Other antibacterial drugs

Fluoroquinolone

bind tobacterialribosomes inhibits

bacterial DNA

replication


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Structure-based Drug Design Cycle

Target identificationand validation

Assay development

Virtual screening (VS)

High throughputscreening (HTS)

Quantitative structure

activity relationship(QSAR) and refinementof compounds

Characterization ofprospective 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 activesite of HIV-1 protease:Agouron's AIDS drug nelfinavir(brand name Viracept) is one of

the drugs on the market that canbe traced directly to structure-based methods.


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Capoten Captopril ACE Hypertension 1981 Bristol-

MyersSquibb

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 Chronicmyelogenous

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 comprisingthree binding pockets

B. Crystallographic screeninglocates molecular

fragments that bind to one,two or all three pockets

C. A lead compound isdesigned by organizing allthree fragments around a

core template

D. Growing out of a singlefragment


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Example Combinatorial Library

NH

R1

R2

R3

Scaffold R-groups

R1 = OHOCH3NH2ClCOOH

R2 = phenyl

OHNH2BrFCN

R3 = CF3

NO2OCH3OHphenoxy

Examples

NH

OH

CN

OH

NH

OH

OCH3

NH

C

OH

OHO

CF3

NH

C

OH

OHO

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


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Similarity Paradox


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Descriptors of

Molecular Structure & Properties 1D-descriptors encode chemical composition &

physicochemical properties

MW, Cm

On

Hk

,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

Pharmacophorethe spatial arrangement of

chemical groups that determines its activity


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Lipinski Rule of Five (1997)

Poor absorption and permeation are more likelyto occur when there are more than 5 hydrogen-bond donors, more than 10 hydrogen-bondacceptors, the molecular mass is greater than500, or the log P value is greater than 5.

Further research studied a broader range ofphysicochemical and structural properties

Related problems: Compound toxicity

Compound mutagenicity

Blood-brain barrier penetration

Central nervous system activity


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In Silico ADME Models

Computational methods can predict compound propertiesimportant 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 primarymetabolism of majority of

drugs in human body -likelyto herald a new era ofstructure-based design in themodulation of metabolicproperties of drugs.

Can metabolism properties be modulated?

strut based drug design-1

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