Dry selection and wet evaluation for the rational discovery of new anthelmintics

作者：Marrero Ponce Yovani; Gonzalez Castaneda Yeniel; Vivas Reyes Ricardo; Maximo Vergara Fredy; Aran Vicente J; Castillo Garit Juan A; Perez Gimenez Facundo; Torrens Francisco; Huong Le Thi Thu; Hai Pham The; Vera Montenegro Yolanda; Ibarra Velarde Froylan

来源：Molecular Physics, 2017, 115(17-18): 2300-2313.

DOI：10.1080/00268976.2017.1296194

• TOMOCOMD-CARDD software
• QuBiLs-MAS module
• free and open source software
• non-stochastic and stochastic atom-based bilinear indices
• LDA-based QSAR model
• computational screening
• lead generation
• anthelmintic activity
• indazole

Helminths infections remain a major problem in medical and public health. In this report, atom-based 2D bilinear indices, a TOMOCOMD-CARDD (QuBiLs-MAS module) molecular descriptor family and linear discriminant analysis (LDA) were used to find models that differentiate among anthelmintic and non-anthelmintic compounds. Two classification models obtained by using non-stochastic and stochastic 2D bilinear indices, classified correctly 86.64% and 84.66%, respectively, in the training set. Equation 1(2) correctly classified 141(135) out of 165 [85.45%(81.82%)] compounds in external validation set. Another LDA models were performed in order to get the most likely mechanism of action of anthelmintics. The model shows an accuracy of 86.84% in the training set and 94.44% in the external prediction set. Finally, we carry out an experiment to predict the biological profile of our in-house' collections of indole, indazole, quinoxaline and cinnoline derivatives (approximate to 200 compounds). Subsequently, we selected a group of nine of the theoretically most active structures. Then, these chemicals were tested in an invitro assay and one good candidate (VA5-5c) as fasciolicide compound (100% of reduction at concentrations of 50 and 10 mg/L) was discovered.

• 出版日期2017