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Abstract  There is evidence that Tetracyclines are potentially useful drugs to treat prion disease, the fatal neurodegenerative disease in which cellular prion proteins change in conformation to become a disease-specific species (PrPSc). Based on an in vitro anti-fibrillogenesis test, and using the peptide PrP106–126 in the presence of tetracycline and 14 derivatives, we carried out a three-dimensional quantitative structure-activity relationship (3D-QSAR) study to investigate the stereoelectronic features required for anti-fibrillogenic activity. A preliminary variable reduction technique was used to search for grid points where statistical indexes of interaction potential distributions present local maximum (or minimum) values. Variable selection genetic algorithms were then used to search for the best 3D-QSAR models. A 6-variable model showed the best predictability of the anti-fibrillogenic activity that highlighted the best tetracycline substitution patterns: hydroxyl group presence in positions 5 and 6, electrodonor substituents on the aromatic D-ring, alkylamine substituent at the amidic group in position 2 and non-epi configuration of the NMe2 group. [ABSTRACT FROM AUTHOR]