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Atom, atom-type and total molecular linear indices as a promising approach for bioorganic and medicinal chemistry: theoretical and experimental assessment of a novel method for virtual screening and rational design of new lead anthelmintic

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Atom, atom-type and total molecular linear indices as a promising approach for bioorganic and medicinal chemistry: theoretical and experimental assessment of a novel method for virtual screening and rational design of new lead anthelmintic
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  Atom, atom-type and total molecular linear indices as apromising approach for bioorganic and medicinal chemistry:theoretical and experimental assessment of a novel methodfor virtual screening and rational design of new lead anthelmintic Yovani Marrero-Ponce, a,b,* Juan A. Castillo-Garit, b,c Ervelio Olazabal, d Hector S. Serrano, d Alcidez Morales, d Nilo Castan˜edo, b,d Froyla´n Ibarra-Velarde, e Alma Huesca-Guillen, e Alicia M. Sa´nchez, a Francisco Torrens f  and Eduardo A. Castro g a Department of Pharmacy, Faculty of Chemical-Pharmacy, Central University of Las Villas, Santa Clara, 54830 Villa Clara, Cuba b Department of Drug Design, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830 Villa Clara, Cuba c Applied Chemistry Research Center, Central University of Las Villas, Santa Clara, 54830 Villa Clara, Cuba d Department of Parasitology, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, 54830 Villa Clara, Cuba e Department of Parasitology, Faculty of Veterinarian Medicinal and Zootecnic, UNAM, Mexico, D.F. 04510, Mexico f  Institut Universitari de Cie` ncia Molecular, Universitat de Vale` ncia, Dr. Moliner 50, E-46100 Burjassot, Vale` ncia, Spain g INIFTA, Divisio´ n Quı´ mica Teo´ rica, Suc.4, C.C. 16, La Plata 1900, Argentina Received 6 October 2004; revised 17 November 2004; accepted 22 November 2004Available online 16 December 2004 Abstract—  Helminth infections are a medical problem in the world nowadays. In this paper a novel atom-level chemical descriptorhas been applied to estimate the anthelmintic activity. Total and local linear indices and linear discriminant analysis were used toobtain a quantitative model that discriminates between anthelmintic and non-anthelmintic drug-like compounds. The discriminantmodel has an accuracy of 90.11% in the training set, with a high Matthews   correlation coefficient (MCC = 0.80). To assess therobustness and predictive power of the obtained model, internal (leave- n -out) and external validation process was performed.The QSAR model correctly classified 88.55% of compounds in this external prediction set, yielding a MCC of 0.77. AnotherLDA model was carried out to outline some conclusions about the possible modes of action of anthelmintic drugs. It has an accu-racy of 93.50% in the training set, and 80.00% in the external prediction set. After that, the developed model was used in the vir-tual—in silico—screening and several compounds from the Merck Index, Negwer  s Handbook and Goodman and Gilman wereidentified by the model as anthelmintic. Finally, the experimental assay of an organic chemical (a furylethylene derivative) by anin vivo test permits us to carry out an assessment of the model. An accuracy of 100% with the theoretical predictions was observed.These results suggest that the proposed method will be a good tool for studying the biological properties of drug candidates duringthe early state of the drug-development process.   2004 Elsevier Ltd. All rights reserved. 1. Introduction Anthelmintic drugs are used to control, prevent, andtreat nematode, cestode, and trematode parasite infesta-tions in humans and domestic animals. 1 Regrettably,with the increased use of these compounds, anthelminticresistance (see Table 1) has appeared and increased in frequency. 2 If resistance to a particular anthelmintichas occurred, it is likely that another anthelmintic withthe same mode of action will also be ineffective althoughother anthelmintics with another mode of action. 3 Moreover, continued economic losses in animal produc-tion and human diseases due to parasites are still of con-cern to industrial chemists looking for new anthelminticagents. 1 The great cost associated with the development 0968-0896/$ - see front matter    2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.bmc.2004.11.040 Keywords : Anthelmintic activity; QSAR;  TOMOCOMD-CARDDTOMOCOMD-CARDD  software;Total and local linear indices; Virtual screening.*Corresponding author. Tel.: +53 42 281192/281473; fax: +53 42281130/281455; e-mail addresses: yovanimp@qf.uclv.edu.cu;ymarrero77@yahoo.esBioorganic & Medicinal Chemistry 13 (2005) 1005–1020  Request the full paper by mail, jacgarit@yahoo.es
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