Tomocomd-Cardd, a novel approach for computer-aided ? rational? drug design: I. Theoretical and experimental assessment of a promising method for computational screening and in silico design of new anthelmintic compounds

Abstract

In this work, the TOMOCOMD-CARDD approach has been applied to estimate the anthelmintic activity. Total and local (both atom and atom-type) quadratic indices and linear discriminant analysis were used to obtain a quantitative model that discriminates between anthelmintic and non-anthelmintic drug-like compounds. The obtained model correctly classified 90.37% of compounds in the training set. External validation processes to assess the robustness and predictive power of the obtained model were carried out. The QSAR model correctly classified 88.18% of compounds in this external prediction set. A second model was performed to outline some conclusions about the possible modes of action of anthelmintic drugs. This model permits the correct classification of 94.52% of compounds in the training set, and 80.00% of good global classification in the external prediction set. After that, the developed model was used in virtual in silico screening and several compounds from the Merck Index, Negwer's handbook and Goodman and Gilman were identified by models as anthelmintic. Finally, the experimental assay of one organic chemical (G-1) by an in vivo test coincides fairly well (100%) with model predictions. These results suggest that the proposed method will be a good tool for studying the biological properties of drug candidates during the early state of the drug-development process.

Atom, Atom-Type, and Total Linear Indices of the “Molecular Pseudograph’s Atom Adjacency Matrix”: Application to QSPR/QSAR Studies of Organic Compounds

“…In the canonical basis, the coordinates of any vector X coincide with the components of this vector [30][31][32][33]. For this reason, those coordinates can be considered as weights (atom labels) of the vertices of the molecular pseudograph [15][16][17][18][19][20][21][22][23].…”

“…Here, M(G) = M = [a ij ], denotes the matrix of f k (x i ) with respect to the natural basis. In this matrix n is the number of vertices (atoms) of G and the elements a ij are defined as follows [15][16][17][18][19][20][21][22][23]:…”

“…The method has also demonstrated flexibility in relation to many different problems. One of the applications involved the prediction of the anthelmintic activity of novel drugs [20]. More recently, the TOMOCOMD-CARDD approach has been applied to the fast-track experimental discovery of novel antimalarial compounds [21].…”

“…One of the applications involved the prediction of the anthelmintic activity of novel drugs [20]. More recently, the TOMOCOMD-CARDD approach has been applied to the fast-track experimental discovery of novel antimalarial compounds [21]. Codification of chirality and other 3D structural features constitutes another advantage of this method [22].…”

A novel non-stochastic quadratic fingerprints-based approach for the ‘in silico’ discovery of new antitrypanosomal compounds

“…[17][18][19] It was, for instance, successfully used on the virtual screening of novel antihelminthic compounds, which were then synthesized and in vivo evaluated on Fasciola hepatica. 20,21 Other studies for the rational discovery of novel paramphistomicides, 22 antimalarial 23 and antibacterial 24 compounds were also conducted with the TOMOCOMD approach. This method has been extended to consider three-dimensional features of small/medium-sized molecules upon the base of the application of a trigonometric 3D-chirality correction factor.…”