Subject: Chem topic: Computational Drug Design

From: David Young <[email-masked]>
Date: Mon, 6 Oct 1997 13:40:17 -0500 (CDT)

Hello all,

	I have written the following short essay for a computational 
chemistry class and am posting it here for your enjoyment and comments.
Since I have not done drug design in an industrial setting, I would
appreciate any comments about which techniques are used most often.

	My compilation of chemical topics can be accessed via the web 
at URL http://www.auburn.edu/~youngd2/topics/contents.html

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			   Computational Drug Design

   			          David Young

		        Division of University Computing
		  	         144 Parker Hall
		          Auburn University, AL  36849

	The purpose of this document is to outline the drug design 
process and specifically the role of computational modeling techniques.
This is not meant to be a comprehensive review.  It is meant to list
the most important techniques currently in use.  

	The process of designing a new drug and bringing it to market
is very complex and can take up to a decade from the start of the process
until a new drug is available to physicians.  Pieces of this process
are often repeated to create successively better drugs for the same
condition.  In the case of antibiotics, drugs loose effectiveness as 
an immunity is built up, thus leading to a continuing "arms race".  The
major steps in the drug design process "from scratch" are.

1.  FIND WHAT IS KNOWN  
Find out all that is known about the disease and existing or traditional 
remedies.  It is also important to look at very similar afflictions and their 
known treatments.

2.  DEVELOP AN ASSAY
Develop an assay technique to test drug effectiveness.  An ideal assay
is one in which a compound can be added to tissue samples or micro-organism 
colonies and there will be a visible indication of an effective treatment.
At worst, there must be a way to test the drug on a laboratory animal
that is susceptible to the disease.  If the only way to test the 
effectiveness of a trial compound is to inject an untested compound into
a human subject then there is no way to proceed in finding a pharmaceutical
treatment.

3.  CONSIDER FINANCIAL ISSUES
The next step is to make a financial decision about whether to proceed
with the development process.  The assay technique will determine the 
cost of testing compounds.  If there are existing chemical treatments, it 
will be a refinement effort which saves the expense of finding lead compounds.
All drugs must go through extensive testing so this is a fairly fixed cost.
There may be governmental grants or tax incentives associated with certain 
diseases.  The number of patients requiring treatment and merits of existing 
treatments will determine the long term profitability of producing a drug.

Steps 4 and 5 of this procedure are often performed simultaneously.

4.  FIND LEAD COMPOUNDS
Lead compounds are compounds that have some activity against a disease.
These may be only marginally useful and may have severe side effects.  
However, the lead compounds provide a starting point for refinement of 
the chemical structures.  Lead compounds may come from many sources, including

	a.  The isolation of active compounds from traditional remedies.

	b.  The testing of natural materials followed by an isolation
	    effort.

	c.  Drugs effective against similar diseases.

	d.  Use of combinatorial chemistry techniques which produce large 
	    numbers of related chemical compounds.  This allows testing a large
	    number of compounds at once.  When a mixture that is useful
	    is found, a separation must be done to determine which of
	    the related structures has some drug activity.  This has been
	    one of the most promising and rapidly growing techniques in
	    recent years.

	e.  Searching chemical databases to find compounds similar to those
	    found by the above means.  This is the only part of the lead 
	    finding process that is considered to be a computational technique.
	    There are many different measures of molecular similarity and
	    ways of efficiently handling large databases, so this is not yet
	    a trivial step.

5.  ISOLATE THE MOLECULAR BASIS FOR THE DISEASE
If it is known that a drug must bind to a particular spot on a particular 
protein or nucleotide then a drug can be tailor made to bind at that site.
This is often modeled computationally using any of several different
techniques.  Traditionally, the primary way of determining what compounds
would be tested computationally was provided by the researchers' understanding
of molecular interactions.  A second method is the brute force testing of
large numbers of compounds from a database of available structures.  

More recently a set of techniques, called rational drug design techniques
or De Novo techniques have been used.  These techniques attempt to reproduce
the researchers' understanding of how to choose likely compounds built into a 
software package that is capable of modeling a very large number of 
compounds in an automated way.  Many different algorithms have been used for
this type of testing, many of which were adapted from artificial 
intelligence applications.  No clear standard has yet emerged in this area
so it is impossible to say what is best the best technique at this time.

These techniques have seen quite a bit of active development in recent 
years.  Unfortunately, the complexity of biological systems makes it very
difficult to determine the structures of large biomolecules.  Ideally a
x-ray chrystallography structure is desired, but biomolecules are very 
difficult to chrystalize.  Another very useful technique, called "distance
geometry" is to find some of the internuclear distances using 
NMR Nuclear Overhauser Effect experiments then find molecular geometries that 
have these distances.  If only a protein sequence is known, there are many
techniques for predicting how that protein will fold, but none has yet been
shown to be 100% reliable.  Even once a structure has been determined, 
identifying the site where a drug must bind is not a trivial task.

The difficulty in find geometries makes it possible to bring first generation 
drugs to market by refinement of lead compounds without ever knowing the 
target site for the drug in the body.  As such, these techniques are being 
used primarily for designing improved treatments for diseases that have 
already been characterized extensively.

6.  REFINE DRUG ACTIVITY
Once a number of lead compounds have been found, computational and laboratory
techniques have been very successful in refining the molecular structures to 
give a greater drug activity and fewer side effects.  This is done both
in the laboratory and computationally by examining the molecular structures to 
determine which aspects are responsible for both the drug activity and the
side effects.

Synthetically, functional groups are removed in order to find out which must
be present to give a useful drug and which are not necessary.  The back bone
of the structure is made more flexible or more rigid.  A rigid back bone may
hold the functional groups in the exact alignment necessary for the drug to
bind.  A flexible back bone may be necessary to allow the drug to get into
the binding site.  Adding bulky groups at other points on the molecule is
often done in the hopes that these new groups may hinder the molecule from 
binding at unwanted sites which are responsible for the side effects.

Computationally, the technique used is known as QSAR (Quantitative 
Structure Activity Relationships).  It consists of computing every possible
number that can describe a molecule then doing an enormous curve fit to
find out which aspects of the molecule correlate well with the drug activity
or side effect severity.  This information can then be used to suggest new
chemical modifications for synthesis and testing.

Ideally there is a continual exchange of information between the researchers
doing QSAR studies, synthesis and testing.  These techniques are frequently
used and often very successful since they do not rely on knowning the 
biological basis of the disease which can be very difficult to determine.

7.  DRUG TESTING
Once a drug has been shown to be effective by an initial assay technique,
much more testing must be done before it can be given to human patients.
Animal testing is the primary type of testing at this stage.  The scientists 
doing the testing must be particularly observant of many little details since
this is where unexpected side effects can be found.  Another question to be
answered is whether the drug will work well or poorly with other drugs.
This is also where initial data necessary to determine correct dosages
is obtained.

Eventually, the compounds which are deemed suitable at this stage are 
sent on to clinical trials.  In the clinical trials, additional side 
effects may be found and human dosages are determined. 

8.  FORMULATION
Before a drug can be produced, there must be a means to administer it.  
Ideally, a tasteless or bland tablet can be created.  Alternatively,
an oral liquid, intravenous injection or directly applied cream may be
created.

Tablets are created by adding other compounds to minimize stomach upset and
control timed release of the drug.  A tablet may also have a compound which
is a matrix that helps it hold it's shape without crumbling into a powder.

Oral liquids are often combined with strong flavors and alcohol to mask
the taste of the drug and prevent throat irritation.

A cream may have to be thickened or have a component that the skin will
absorb readily.

9.  PRODUCTION
The large scale production of complex molecules can be very difficult.
Compounds originally isolated from natural products may continue to
be harvested.  Often natural products are found in nature only in extremely
small quantities necessitating a complex synthesis.  One route that has been
under development more recently is to have compounds produced by genetically
engineered micro-organisms or plants.

Drugs have a high value per gram.  As such production techniques can be
viable even though they are far more inefficient than those used by bulk
chemical producers.  Often all possible production techniques are researched
even though only one will be put into practice.  This is done so that there
are no openings for competing corporations to get around a manufacturers
patents by using a different technique.

10.  MARKETING
If there is only one available treatment for a disease, it is only necessary
to see that physicians know about it.  If there are several competing 
treatments, there may be quite a bit of marketing done so that physicians
will understand the relative merits of each.

11.  NON-PERSCRIPTION SALES
After a large amount of experience under a physicians supervision, a
drug may be approved for over-the-counter sales.  This is often the
biggest profit making end of the pharmaceutical industry.

12.  GENERIC PRODUCTION
Once the chemical patents have expired, a drug can be produced by any
manufacturer.  Generic drugs are often less expensive for the consumer 
and yield a low profit margin for the producer.  The production of generic 
drugs favors the most cost effective production process.

REFERENCES

A good book over all, and chapter 7 in particular, is 
G. L. Patrick "An Introduction to Medicinal Chemistry" Oxford (1995)

An introduction to computational techniques is
G. H. Grant, W. G. Richards "Computational Chemistry" Oxford (1995)

A more detailed description of computational techniques is
A. R. Leach "Molecular Modelling Principles and Applications" Longman (1996)

L. Balbes' "Guide to Rational (Computer-aided) Drug Design" is at
gopher://www.ccl.net/00/documents/drug.design.guide

There are many links on Soaring Bear's web page at
http://ellington.pharm.arizona.edu/%7Ebear/

An introduction to structure-based techniques is
I. D. Kuntz, E. C. Meng, B. K. Shoichet Acct. Chem. Res. 27 (5), 117 (1994)

An introduction to De Novo techniques is
S. Borman Chemical and Engineering News 70 (12), 18 (1992)

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