Discovering rules for the inhibition of E. Coli Dihydrofolate Reductase
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Inhibition of E. Coli Dihydrofolate Reductase
The data here concerns the classic drug design problem of inhibition of
E. Coli Dihydrofolate Reductase by pyrimidines and triazines. Pyrimidine
compounds are antibiotics. They act by inhibiting Dihydrolate Reductase,
an enzyme on the pathway to forming DNA. They inhibit bacterial forms of
the enzyme preferentially to the human form and therefore kill bacteria.
This research has been performed jointly with the Imperial
Cancer Research Fund Biomolecular Modelling (BMM) Laboratory. Further
details on using ILP for this problem are available in [King
R.D, Muggleton S., and Sternberg M.J.E. (1992)] and [King,
R.D., Srinivasan, A. and Sternberg, M.J.E. (1995)].
The Pyrimidine problem
The pyrimidine problem is as follows. The chemical structures of all the
compounds used to induce the Structure Activity Relationship
(SAR) can be considered to have a common template. To this template,
chemical groups can be added at three possible substitution positions,
3, 4, and 5. A chemical group is an atom or set of structurally connected
atoms that can be substituted together as a unit and have well defined
chemical properties. In the following diagram, the first structure is the
generic pyrimidine template and the second is an example compound, with
3=Cl, 4=NH2, 5=CH3.
The existence of a template with only three possible substitution positions
gives the pyrimidine problem a relatively small structural component. The
chemical structure of the example compound above is adequately represented
by a Prolog fact of the form
struc( d55, cl, nh2, ch3 )
which is intended to represent that drug 55 has a chlorine atom substituted
at position 3, an amine group (NH2) group substituted at position 4, and
a methyl (CH3) group at position 5.
In [King R.D, Muggleton S., and Sternberg M.J.E. (1992)],
the authors use 9 integer-valued attributes to represent chemical properties
of the substituents. These were encoded as predicates of the form:
polar( br, polar3 )
which states that a bromine atom has a polarity of value 3.
Positive examples are pairs of drugs, the activity of one being known
to be higher than the other. For example:
great( d1, d2 )
states that the E. Coli Dihydrofolate Reductase inhibition by drug d1
is higher than that by d2.
The Triazine problem
A more difficult problem concerns the inhibition of E. Coli Dihydrofolate
reductase by triazines. Triazines act as anti-cancer agents by inhibiting
the enzyme Dihydrolate Reductase. They act by preferentially inhibiting
reproducing cells. Like the pyrimidines, the triazines can also be considered
to have a common template structure, shown below. However, the chemical
groups substituted onto the template are much more complicated than the
pyrimidine drugs. Further, many of the substituting groups can more naturally
be considered as sub- templates with substitutions. There are seven (7)
regions where a substituent might be present: the 2, 3, and 4 positions
of the phenyl ring as shown below. Each substituent can in turn, itself
contain a ring structure. In this case, further substitutions are possible
into positions 3 and 4 of these rings.
In the following diagram of triazine structures, the first structure
is a generic template for all compounds in the study, and the second is
an example with 3=Cl, 4=(CH2)2 C6H3-4-Cl, 5=CH3
The first-order representation of the triazines is best explained using
an example. The example compound above is represented by the following
struc3( d217,cl, absent ).
struc4( d217, '(ch2)4', subst14 ).
subst( subst14, so2f, cl ).
The first clause represents substitutions at position 3 on the basic template:
a Cl is present and there is an absence of a further phenyl ring. The second
clause represents substitutions at position 4 on the basic template: there
is a (CH2)4 bridge to a second phenyl ring (implicit in the representation).
This second phenyl ring has an S02F group substituted at position 3 and
a Cl group substituted at position 4. This is represented using the linker
constant subst14 to the third clause. There is no substitution
at position 2 on the basic template. Each of the chemical groups had 10
attributes, 9 of which were the same as used in the study of pyrimidines.
One further attribute was added to capture flexibility of a substituent.
The degree of flexibility is represented by one of 9 values.
The Golem datasets
The data files are stored in one
compressed TAR file. within that, they are as used in the original
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.
King R.D, Muggleton S., and Sternberg M.J.E.
Drug design by machine learning: The use of inductive logic programming
to model the structure-activity relationships of trimethoprim analogues
binding to dihydrofolate reductase.
Proc. of the National Academy of Sciences, 89(23):11322--11326,
King, R.D., Srinivasan, A. and Sternberg,
Relating chemical activity to structure: an examination of ILP successes.
New Gen. Comput. (to appear).
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