LECTURE 10

Contents

In silico drug design

Basic terminology

Pharmacon (Gr. φάρµακον = drug ): a compound affectingliving organismsPharmacy: is a transitional field between health sciencesand chemical sciencesPharmacology: (Gr. λόγος = science): is the study of how substances interact with living organisms to produce a changein function.

Main points in history

16th century – Iatrochemistry(Paracelsus)

“…only the dose permits something not to be poisonous. “

18th century allopathy: treating symptoms, this is the traditional medicine, where a disease istreated by producing a second conditionthat is incompatible with or antagonisticto the first

19th century homeopathy (Hahnemann):treating the sick with extremely dilutedagents that, in undiluted doses, producesimilar symptoms in the healthy

1850 Pharmacodynamics, homeostasis(Claude Bernard)"To have a free life, independentof the external environment,requires a constant internalenvironment"

Which parameters should be optimized during drug development?Pharmacodynamics: is the study of the biochemical and physiological effects of drugs and the mechanisms of drug action and the relationship between drug concentration and effect.Pharmacokinetics: the study of the time course of substances and their relationship with an organism or system (ADME)

Possibilities of drug discovery

-“Accidentally” (e.g. penicillin, antibacterialby Fleming)

- Using biochemical knowledge(e.g. allopurinol against gout)

- Screening (experimental or virtual)

In silico (computational) methods helps to reduce the- monetary costs- amount of experiments and waste chemicals- amount of killed animals

Costs of drug discovery- 400-800 million $, 75 % of which goes for useless drug

↓↓↓↓

28 % lack of efficiency, 5 % bad marketing strategy,20 % toxicity, 37 % bad pharmacokinetics

- Chemicals and biohazards (environmental problems)- Killed animals (ethical problems)

Drug design strategies

Merck

Pfizer-Groton(HTS)

Trends in drug design

Merck

Pfizer-Groton(HTS)

Hierarchy of in silico methods

PharmacokineticsAbsorptionDistributionExcretion

Pharmacodynamics

1D/2D

1D/2D

Ghose et al. (Comprehensive Medicinal Chemistry Database)80 %

-0.4≤AlogP ≤5.6 (average: 2.52)

160≤MW ≤480 (average: 357)

20≤number of atoms ≤70 (average: 48)

The 1D/2D filters areimplemented in programpackages.

BBB (Blood Brain Barrier) penetration of drugs

Complex cell system formed by the endothel cells of braincapillaries. Maintains the homeostasis of central nervous system.BBB should allow drugs acting on central nervous system butnot the periferial drugs.

logBB=-0.148PSA+0.152ClogP+0.139n=55 r2=0.79

logBB=-0.0322PSA+1.33n=45 r2=0.84

logBB=0.423-0.0171TPSA+0.000822MWn=55 r2=0.703

Metabolism of xenobiotics

The structure of cytochrome (CYP) 3A4complexed with progesteron

NADPH + H+ + O2 + Drug =NADP+ + H2O + Oxidized Drug

CYP Fe+2

Drug

O2

CYP Fe+3

OHDrug

2H

+H2O

Toxicity

Nitrils

-logLD50=-1.69α/∆E+0.47N=13 r=0.87(α:polarizability ∆E:HOMO-LUMO diff.

Substituted benzenes

log(1/LC50)=-1.49+0.56logP+13.7SDELOCN=114 r2=0.81

ADMETox

Painful lessons

Nature Structural & Molecular Biology 12, 205 (2005)

The risk of heart attacks and strokes associated with Vioxx and Celebrex

reminds us that all drugs have side effects.

The serious side effects of pain relievers have been in the news lately.

The increased risk of heart attacks and strokes associated with

rofecoxib (Vioxx, Merck) and celecoxib (Celebrex, Pfizer) has led to the

withdrawal of rofecoxib in late 2004 (the largest withdrawal in history)

and reduced the sales of celecoxib by 50%.

Because rofecoxib and celecoxib are top-selling prescription medicines,

the issue has drawn widespread response. At a US congressional hearing,

we heard testimony that the FDA failed to protect the public from unsafe

drugs.

Similar to the development of imatinib (Gleevec, Novartis), the success

of rofecoxib and celecoxib validated the concept that drugs targeted to

specific molecules have fewer side effects, at least until recently. The

problem facing rofecoxib and celecoxib—that they avoided gastric

bleeding only to incur the severe side effects of heart attacks and

strokes—seems to contradict this particular strategy.

Nevertheless, the case is a clear reminder that all drugs have side

effects; the question is whether their benefits outweigh their risks.

Side-effects of drugs(some statistics)

A clinical patient consumes an average of 15 drugs.

Doctors order some kind of drugs for 75 % of their patients.

Antibiotics consumed in hospitals are unnecessary in 64 % ofthe cases.

A 15 % of clinical patients suffer from side-effects and a 5 %becomes a clinical case because of side-effects.

Selectivity and inverse docking

Summary

“Theories are only verified hypotheses, verified by more or lessnumerous facts. Those verified by the most facts are the best,but even then they are never final, never to be absolutely believed.”(C. Bernard)

Structure

OptimizedStructure+ Energy

(∆∆∆∆G)

Other Properties‘Drug-likeness’

ADMEToxSide-effects

etc.