Non-stochastic quadratic fingerprints and LDA-based QSAR models in hit and lead generation through virtual screening: theoretical and experimental assessment of a promising method for the discovery of new antimalarial compounds.

In order to explore the ability of non-stochastic quadratic indices to encode chemical information in antimalarials, four quantitative models for the discrimination of compounds having this property were generated and statistically compared. Accuracies of 90.2% and 83.3% for the training and test sets, respectively, were observed for the best of all the models, which included non-stochastic quadratic fingerprints weighted with Pauling electronegativities. With a comparative purpose and as a second validation experiment, an exercise of virtual screening of 65 already-reported antimalarials was carried out. Finally, 17 new compounds were classified as either active/inactive ones and experimentally evaluated for their potential antimalarial properties on the ferriprotoporphyrin (FP) IX biocrystallization inhibition test (FBIT). The theoretical predictions were in agreement with the experimental results. In the assayed test compound C5 resulted more active than chloroquine. The current result illustrates the usefulness of the TOMOCOMD-CARDD strategy in rational antimalarial-drug design, at the time that it introduces a new family of organic compounds as starting point for the development of promising antimalarials.

[1]  M Read,et al.  Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria. , 1998, Journal of medicinal chemistry.

[2]  M. Wolff,et al.  BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY , 1996 .

[3]  Humberto González-Díaz,et al.  Biopolymer stochastic moments. I. Modeling human rhinovirus cellular recognition with protein surface electrostatic moments , 2005, Biopolymers.

[4]  Richard A. Johnson,et al.  Applied Multivariate Statistical Analysis , 1983 .

[5]  H. Ginsburg,et al.  A non-radiolabelled ferriprotoporphyrin IX biomineralisation inhibition test for the high throughput screening of antimalarial compounds. , 2002, Experimental parasitology.

[6]  Yovani Marrero-Ponce,et al.  Non-stochastic and stochastic linear indices of the 'molecular pseudograph's atom adjacency matrix': application to 'in silico' studies for the rational discovery of new antimalarial compounds. , 2005, Bioorganic & medicinal chemistry.

[7]  Vicente Romero Zaldivar,et al.  Total and Local Quadratic Indices of the “Molecular Pseudograph’s Atom Adjacency Matrix”. Application to Prediction of Caco-2 Permeability of Drugs , 2003 .

[8]  J. Ruiz,et al.  Approaches to 1,1-disubstituted cinnolin-3-ylio oxides: synthesis and reactivity of a new class of heterocyclic betaines , 1997 .

[9]  Pierre Baldi,et al.  Assessing the accuracy of prediction algorithms for classification: an overview , 2000, Bioinform..

[10]  Ernesto Estrada,et al.  A novel approach for the virtual screening and rational design of anticancer compounds. , 2000, Journal of medicinal chemistry.

[11]  Han van de Waterbeemd,et al.  Chemometric methods in molecular design , 1995 .

[12]  Yovani Marrero-Ponce,et al.  Ligand-Based Virtual Screening and in Silico Design of New Antimalarial Compounds Using Nonstochastic and Stochastic Total and Atom-Type Quadratic Maps , 2005, J. Chem. Inf. Model..

[13]  J. Ruiz,et al.  Synthesis of Quaternary Indoxyl Derivatives by Intramolecular Cyclization of Some Substituted Acetophenones , 1994 .

[14]  M. C. Vega,et al.  A novel non-stochastic quadratic fingerprints-based approach for the ‘in silico’ discovery of new antitrypanosomal compounds , 2005 .

[15]  R. Chicharro,et al.  Synthesis of quinoxaline derivatives from substituted acetanilides through intramolecular quaternization reactions , 2002 .

[16]  J. Gálvez,et al.  New hypoglycaemic agents selected by molecular topology. , 2004, International journal of pharmaceutics.

[17]  V. Arán,et al.  Analogues of Cytostatic, Fused Indazolinones: Synthesis, Conformational Analysis and Cytostatic Activity Against HeLa Cells of Some 1-Substituted Indazolols, 2-Substituted Indazolinones, and Related Compounds , 2006 .

[18]  E Estrada,et al.  In silico studies for the rational discovery of anticonvulsant compounds. , 2000, Bioorganic & medicinal chemistry.

[19]  T. Saibara,et al.  Effect of Sho‐saiko‐to Extract on HGF and TGF‐β Levels of Intraorgans in Liver‐injured Rats after Partial Hepatectomy , 2000, The Journal of pharmacy and pharmacology.

[20]  P. Wilairat,et al.  Structure-activity relationships of some indolo[3,2-c]quinolines with antimalarial activity. , 1998, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[21]  Francisco Torrens,et al.  3D-chiral quadratic indices of the 'molecular pseudograph's atom adjacency matrix' and their application to central chirality codification: classification of ACE inhibitors and prediction of sigma-receptor antagonist activities. , 2004, Bioorganic & medicinal chemistry.

[22]  Yovani Marrero Ponce.  Total and Local Quadratic Indices of the Molecular Pseudograph’s Atom Adjacency Matrix: Applications to the Prediction of Physical Properties of Organic Compounds , 2003, Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry.

[23]  A. Balaban,et al.  Topological Indices and Related Descriptors in QSAR and QSPR , 2003 .

[24]  Yovani Marrero-Ponce,et al.  A linear discrimination analysis based virtual screening of trichomonacidal lead-like compounds: outcomes of in silico studies supported by experimental results. , 2005, Bioorganic & medicinal chemistry letters.

[25]  Ramón García-Domenech,et al.  Designing sedative/hypnotic compounds from a novel substructural graph-theoretical approach , 1998, Journal of computer-aided molecular design.

[26]  Paola Gramatica,et al.  New 3D Molecular Descriptors: The WHIM theory and QSAR Applications , 2002 .

[27]  J. Walsh.  Disease Problems in the Third World , 1989, Annals of the New York Academy of Sciences.

[28]  R García-Domenech,et al.  Discovery of New Antimalarial Compounds by use of Molecular Connectivity Techniques , 1999, The Journal of pharmacy and pharmacology.

[29]  Lourdes Santana,et al.  3D QSAR Markov model for drug-induced eosinophilia--theoretical prediction and preliminary experimental assay of the antimicrobial drug G1. , 2005, Bioorganic & medicinal chemistry.

[30]  S. Meshnick,et al.  Syntheses and antimalarial activities of N-substituted 11-azaartemisinins. , 1995, Journal of medicinal chemistry.

[31]  J. Ruiz,et al.  Heterocyclization of N′,N′‐Disubstituted 2‐Halogenobenzohydrazides to 1,1‐Disubstituted Indazol‐3‐ylio Oxides. , 1993 .

[32]  J. Cumming,et al.  Orally active antimalarial 3-substituted trioxanes: new synthetic methodology and biological evaluation. , 1998, Journal of medicinal chemistry.

[33]  J. Ruiz,et al.  Reactivity of 1,1-disubstituted indazol-3-ylio oxides: synthesis of some substituted indazolols and indazolinones , 1993 .

[34]  L. Pauling.  The Nature Of The Chemical Bond , 1939 .

[35]  Yovani Marrero-Ponce,et al.  Linear Indices of the "Molecular Pseudograph's Atom Adjacency Matrix": Definition, Significance-Interpretation, and Application to QSAR Analysis of Flavone Derivatives as HIV-1 Integrase Inhibitors , 2004, J. Chem. Inf. Model..

[36]  J. Ruiz,et al.  Cytostatic activity against HeLa cells of a series of indazole and indole derivatives; synthesis and evaluation of some analogues , 1995 .

[37]  Francisco Torrens,et al.  Atom, atom-type, and total nonstochastic and stochastic quadratic fingerprints: a promising approach for modeling of antibacterial activity. , 2005, Bioorganic & medicinal chemistry.

[38]  Yovani Marrero Ponce.  Total and local (atom and atom type) molecular quadratic indices: significance interpretation, comparison to other molecular descriptors, and QSPR/QSAR applications. , 2004, Bioorganic & medicinal chemistry.