The application of ligand-based drug design methods such as quantitative structure–activity relationship
(QSAR) is a mandatory issue in the design of luteinizing hormone-releasing hormone (LHRH) receptor antagonists because
the lack of information on the molecular structure for this target protein. The relationship between the structures and
the antagonistic activities of 128 non-peptide antagonists for the LHRH receptor were modeled by using the classic QSAR
methods comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).
The best model included CoMSIA steric, electrostatic, hydrophobic and hydrogen bond donor fields, had a Q2 value
of 0.780 and predicted adequately the activity of external compounds. The tridimensional contour maps generated were
used to identify the key structural requirements responsible for a high biological activity of the compounds. These features
should represent the ligand features involved in interactions with the target protein that modulate their potency as antagonists.