Fragment-Based Hologram QSAR Studies on a Series of 2,4-Dioxopyrimidine-1-Carboxamides As Highly Potent Inhibitors of Acid Ceramidase

Document Type: Research article

Authors

1 College of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China

2 College of Chemistry and Chemical Engineering Hunan Engineering Institute, Xiangtan, 411104, P.R. CHINA

3 College of Chemistry and Chemical Engineering, Hunan Institute of Engineering, Xiangtan, Hunan 411104, China

Abstract

A series of structurally related 2,4-dioxopyrimidine-1-carboxamide derivatives as highly potent inhibitors against acid ceramidase were subjected to hologram quantitative structure-activity relationship (HQSAR) analysis. A training set containing 24 compounds served to establish the HQSAR model. The best HQSAR model was generated using atoms, bond, connectivity, donor and acceptor as fragment distinction and 3–6 as fragment size with six components showing cross-validated q2 value of 0.834 and conventional r2 value of 0.965. The model was then employed to predict the potency of test set compounds that were excluded in the training set, and a good agreement between the experimental and predicted values was observed exhibiting the powerful predictable capability of this model ( r2pred = 0.788 ). Atom contribution maps indicate that the electron-withdrawing effects at position 5 of the uracil ring, the preferential acyl substitution at N3 position and the substitution of eight-carbon alkyl chain length at N1 position predominantly contribute to the inhibitory activity. Based upon these key structural features derived from atom contribution maps, we have designed novel inhibitors of acid ceramidase possessing better inhibitory activity.

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