The dependence of hydrolytic activity of artificial ribonucleases toward an HIV-I RNA fragment, a 21-mer oligonucleotide, and tRNA Asp on the structure of the RNase mimetic was analyzed. The quantitative structure-activity relationship (QSAR task) was determined by the method of simplex representation of the molecular structure where the amounts of four-atom fragments (simplexes) of fixed structure, symmetry, and chirality served as descriptors. Not only the types of atoms participating in simplexes but also their physicochemical properties (e.g., partial charges, lipophilicities, etc.) were taken into account. This allowed the estimation of the relative role of various factors affecting the interaction of molecules under study with the corresponding biological target. The 2D QSAR models obtained by the method of projection to latent structures have quite satisfactory statistical indices (R2 = 0.82-0.96; Q2 = 0.73-0.89), which help predict the activities of new compounds. The electrostatic properties of ribonuclease atoms were shown to contribute significantly to the manifestation of the hydrolytic activity of ribonucleases in the case of the 21-mer oligonucleotide and tRNA. In addition, the structural fragments that most greatly contribute to the alteration of the hydrolytic activity of RNases were identified. The models obtained were used for the virtual screening and molecular design of new highly efficient RNase mimetics.