Pharmacophore discovery for ACE (angiotensin-converting enzyme) inhibition (OxUni)

Application domain: Pharmacophore discovery for ACE inhibition
Further specification: Data set describing 28 molecules with 3-dimensional atom/bond facts
Pointers: Contact David Page
Data complexity: 77 KB (ASCII)
Data format: Progol

The data

The 28 molecules constitute a diverse set of ACE-inhibitors. ACE-inhibition is a method for the treatment of hypertension.

A pharmacophore for a given activity (such as ACE-inhibition) is a structural property that causes the activity. Pharmacophores are typically described in terms of types of atoms (e.g., hydrogen donors) or functional groups and the pairwise distances among them. The pairwise distances define the geometric arrangement of the atoms or groups that is necessary for them to lock into a particular site of a protein such as ACE. It has long been known that zinc-binding is important for ACE-inhibition. Hydrogen donors and acceptors, and hydrophobic groups should be considered potentially relevant for any pharmacophoric discovery problem.

The 28 molecules in this data set are represented by ``atom'' facts that describe the types of atoms and their x,y,z coordinates. Also present are ``bond'' facts telling which atoms are bonded to each other and telling the types of these bonds. From this information all other necessary information (i.e., types of atoms and groups present in the molecule, pairwise distances between atoms or groups) can be computed. Background predicates were specified that allow the inference of this information.

The experiments

Experiments were performed with P-Progol learning from positive examples only. Constraints were used to specify that clauses are sought that have at least three and at most five pharmacophore pieces (zinc-binder, hacceptor or hdonor) and specify the distances between all pairs of pieces. Three error levels were considered: 0.5, 0.75 and 1 Angstrom.

P-Progol discovered a four-piece pharmacophore with one zinc-binder and three hydrogen acceptors. This pharmacophore appears in all 28 molecules at the 0.75 and 1 Angstrom levels, and 27 molecules at the 0.5 Angstrom level. According to a pharmaceutical expert, this pharmacophore is equivalent to the generally accepted pharmacophore for ACE inhibition.


  1. S. Muggleton, C.D. Page, and A. Srinivasan. An initial experiment into stereochemistry-based drug design using ILP. In S. Muggleton, editor, Proceedings of the 6th International Workshop on Inductive Logic Programming, pages 245-261. Stockholm University, Royal Institute of Technology, 1996.

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