English: Molecule 1 is used as the query molecule. Seven structurally related molecules to molecule 1 are found by similarity searching. Since the target of the query molecule (molecule 1) is unknown, information on the target, structure-activity relationship and pharmacophore are collected for the eight structurally related molecules. Then we consider the following assumptions:

Molecules 3 and 4 have the target of Y. Molecule 3 consists of a square attached to a pentagon with two double bonds, and molecule 4 consists of a triangle attached to a pentagon with two double bonds. Based on information on the structure-activity relationship of molecule 3, the double bonds on the pentagon with two double bonds (cyclopentadiene) must not be reduced. Therefore, the core of these two molecules is the common and important part, named the pentagon with two double bonds (cyclopentadiene). The core of molecules 3 and 4 in the presence of square and triangle is attributed to the pentagon with two double bonds. As a result, the pentagon with two double bonds has priority over the square and the triangle in expressing the target of the molecule. Molecules 5 and 7 have the target of Z. Molecule 5 consists of a square attached to a six-membered aromatic ring (benzene) and a pentagon with two double bonds (cyclopentadiene), and molecule 7 consists of a triangle attached to a five-membered aromatic ring (pyrrole) and a square. Based on information on the structure-activity relationship of molecule 7, the aromatic ring plays an important role in the activity. Therefore, the core of these two molecules is the common and important part, named the aromatic ring (the aromatic ring in molecules 5 and 7 is characterized by LigandScout with AR). There is the pentagon with two double bonds in molecules 3, 4 and 5, but the core of molecule 5 is attributed to the aromatic ring. As a result, the aromatic ring has priority over the pentagon with two double bonds (cyclopentadiene) in expressing the target of the molecule. Molecules 2 and 6 have the target of X. Molecule 2 consists of a triangle attached to a square, and molecule 6 consists of a triangle attached to two squares. Because there is no molecule with the target of X having the square or the triangle alone, so the core of these two molecules is the common part, named the triangle attached to the square. The triangle attached to the square is also present in molecule 7, but the core of this molecule is attributed to the aromatic ring. As a result, the aromatic ring has priority over the triangle attached to the square in expressing the target of the molecule. Molecules 1 and 8 have an unknown target. Molecule 1 consists of a square attached to a triangle and a pentagon, and molecule 8 consists of a square attached to two triangles. There is also a triangle attached to a square (or a square attached to a triangle) in molecules 2, 6 and 7. In addition, the results showed that the aromatic ring and possibly the pentagon with two double bonds (cyclopentadiene) have priority over the triangle attached to the square in expressing the target of the molecule, but molecules 1 and 8 don’t contain any of the aromatic ring or the pentagon with two double bonds. Therefore, the core of molecules 1 and 8 consists of the triangle attached to the square (cyclopropylcyclobutane) and the peripheral part does not consist the aromatic ring and the pentagon with two double bonds (cyclopentadiene). As a result, the target of molecules 1 and 8 is identical to the target of their neighbor molecules, named molecules 2 and 6, and the target of the two molecules is predicted as X.

Abbreviations: AR, aromatic ring; H, hydrophobic interaction; HBD, hydrogen bond donor.

Reference: Forouzesh, Abed; Samadi Foroushani, Sadegh; Forouzesh, Fatemeh; Zand, Eskandar (2019). "Reliable target prediction of bioactive molecules based on chemical similarity without employing statistical methods". Frontiers in Pharmacology. 10: 835. doi:10.3389/fphar.2019.00835