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\section*{Learning rules for comparing drug activities}
The majority of pharmaceutical
R\&D is based on finding slightly improved variants
of patented active drugs (292 out of 348 US drugs
introduced between 1981 and 1988 were of this kind).
This involves laboratories of chemists synthesising and testing
hundreds of compounds. The ability
to automatically discover the chemical properties
which affect the activity of drugs could provide a great
reduction in pharmaceutical R\&D costs.
The average cost of developing a single
new drug is \$230 million.

Alzheimer's disease has long been recognised as one of the most
disabling conditions affecting the aged. It is the major cause of
dementia among elderly people. The drug Tacrine has drawn considerable
attention because of a report of its clinical efficacy for this problem.
This is structure of Tacrine
\begin{figure*}[htb]
\centerline{\epsfbox{tacrine.eps}}
\end{figure*}

Large-scale clinical trials however show that the primary disadvantage of 
Tacrine is its high toxicity. This has led to investigations into
possible variants of the basic Tacrine structure. Variations reported
used the following structure
\begin{figure*}[htb]
\centerline{\epsfbox{new_drug.eps}}
\end{figure*}

New compounds are created by substituting chemicals for ``R'' and ``X''.
The substitution for ``X'' can be in position 6 or 7. The literature
reports on experiments with a number of drugs. The experiments were concerned
with testing various properties of the drugs. A good drug
should have the following properties:
\begin{itemize}
\item Low toxicity.
\item High acetocholinesterase (!) inhibition.
\item Good reversal of scopolamine induced deficiency.
\item Inhibit amine re-uptake.
\end{itemize}

Data from the chemical literature \cite{drugs:alzh} was converted
into a representation suitable for ILP.
More details on the ILP experiments are available in \cite{ashking:newgen}.
The literature does not indicate any particular pattern followed in
creating these new drugs. The plan is to learn rules that tell
us what makes a drug have a desirable property (for example, low
toxicity). Hopefully, these rules will offer better guidance for
the synthesis of a new drug. 

Rules are to be learnt for each property using the 
following information:
\begin{itemize}
\item The positive and negative examples are pairwise comparisons
	of drugs. There are different sets of examples for each
	property.
\item Physical and chemical properties of chemicals that can be substituted for
	``R'' or ``X'' are described by unary predicates in the background knowledge.
	These properties include hydrophobicity, hydrophilicity,
	charge, size, polarity, whether a chemical is aliphatic or aromatic, whether
	it is a hydrogen donator or acceptor etc.
\item Sizes, hydrophobicities, polarities etc., are represented by constants
        (for example, polar0, polar1 etc.).
\item Relations between the constants (less\_than(polar0,polar1)) is
        also provided as background knowledge. 
\item {\bf x\_subst(Drug,Position,Subs)}. The ``X'' substitution for Drug in
	position Position is Subs.
\item The ``R'' substitution is split into parts corresponding to bonds
	between different chemical structures.
\item Sometimes the ``R'' substitution involves the presence of 1 or more
	ring structures. These are benzyl derivatives that arise from
	substitutions within the basic benzene ring structure. The number
	of such substitutions in the basic benzene structure, the position
	of the substitutions an the actual substituent are provided.
\end{itemize}

The data files are stored in a compressed TAR file, which will detar
into several directories. The files themselves are
as used in the original {\em Golem\/} \cite{mugfeng:golem}
experiments. That is, background knowledge files have a ``.b'' suffix,
positive example files have a ``.f'' suffix, and negative example files
have a ``.n'' suffix. 

\begin{thebibliography}{}

\bibitem{ashking:newgen}
King, R.D., Srinivasan, A. and Sternberg, M.J.E. (1995).
Relating chemical activity to structure: an examination of ILP successes.
{\sl New Gen. Comput.} (to appear).

\bibitem{mugfeng:golem}
Muggleton S.H. and Feng C. (1990).
Efficient induction of logic programs.
{\sl Proceedings of the First Conference on Algorithmic Learning Theory},
Tokyo.

\bibitem{drugs:alzh}
Shutske G.M., Pierrat F.A., Kapples K.J., Cornfeldt M.L.,
Szewczak M.R., Huger F.P., Bores G.M., Haroutunian V. and Davis K.L. (1989).
9-Amino-1,2,3,4-tetrahydroacridin-1-ols: Synthesis and Evaluation as Potential
Alzheimer's Disease  Therapeutics.
{\sl J. Med. Chem.}, 32:1805--1813.


\end{thebibliography}

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