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 Prolog facts:

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.

Bibliography

King R.D, Muggleton S., and Sternberg M.J.E. (1992).
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, M.J.E. (1995).
Relating chemical activity to structure: an examination of ILP successes.
New Gen. Comput. (to appear).

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