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Bond-based 2D TOMOCOMD-CARDD approach for drug discovery: aiding decision-making in ‘in silico’ selection of new lead tyrosinase inhibitors

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Abstract

In this paper, we present a new set of bond-level TOMOCOMD-CARDD molecular descriptors (MDs), the bond-based bilinear indices, based on a bilinear map similar to those defined in linear algebra. These novel MDs are used here in Quantitative Structure–Activity Relationship (QSAR) studies of tyrosinase inhibitors, for finding functions that discriminate between the tyrosinase inhibitor compounds and inactive ones. In total 14 models were obtained and the best two discriminant functions (Eqs. 32 and 33) shown globally good classification of 91.00% and 90.17%, respectively, in the training set. The test set had accuracies of 93.33% and 88.89% for the models 32 and 33, correspondingly. A simulated virtual screening was also carried out to prove the quality of the determined models. In a final step, the fitted models were used in the biosilico identification of new synthesized tetraketones, where a good agreement could be observed between the theoretical and experimental results. Four compounds of the novel bioactive chemicals discovered as tyrosinase inhibitors: TK10 (IC50 = 2.09 μM), TK11 (IC50 = 2.61 μM), TK21 (IC50 = 2.06 μM), TK23 (IC50 = 3.19 μM), showed more potent activity than l-mimose (IC50 = 3.68 μM). Besides, for this study a heterogeneous database of tyrosinase inhibitors was collected, and could be a useful tool for the scientist in the domain of tyrosinase enzyme researches. The current report could help to shed some clues in the identification of new chemicals that inhibits enzyme tyrosinase, for entering in the pipeline of drug discovery development.

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Acknowledgments

One of the authors (M-P. Y) thanks the program ‘Estades Temporals per a Investigadors Convidats’ for a fellowship to work at Valencia University (2006–2007). M-P. Y thanks are also given to the Generalitat Valenciana, (Spain) for partial financial support as well as support from Spanish MEC (Project Reference: SAF2006-04698). MTHK is the recipient of a grant from MCBN-UNESCO (grant no. 1056), and fellowships from CIB (Italy) and Associasione Veneta per la Lotta alla Talassemia (AVTL, Italy). F. T. acknowledges financial support from the Spanish MEC DGI (Project No.CTQ2004-07768-C02-01/BQU) and Generalitat Valenciana (DGEUI INF01-051 and INFRA03-047, and OCYT GRUPOS03-173.

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Authors and Affiliations

  1. Institut Universitari de Ciència Molecular, Universitat de València, Edifici d’Instituts de Paterna, Poligon la Coma s/n (detras de Canal Nou), P.O. Box 22085, 46071, Valencia, Spain

    Yovani Marrero-Ponce & Francisco Torrens

  2. Unit of Computer-Aided Molecular “Biosilico” Discovery and Bioinformatic Research (CAMD-BIR Unit), Faculty of Chemistry-Pharmacy, Department of Drug Design, Chemical Bioactive Center, Central University of Las Villas, Santa Clara, Villa Clara, 54830, Cuba

    Yovani Marrero-Ponce & Gerardo M. Casañola-Martín

  3. Unidad de Investigación de Diseño de Fármacos y Conectividad Molecular, Departamento de Química Física, Facultad de Farmacia, Universitat de València, Valencia, Spain

    Yovani Marrero-Ponce & Ramón García-Domenech

  4. Pharmacology Research Lab., Faculty of Pharmaceutical Sciences, University of Science and Technology, Chittagong, Bangladesh

    Mahmud Tareq Hassan Khan

  5. Department of Pharmacology, Institute of Medical Biology, University of Tromso, Tromso, 9037, Norway

    Mahmud Tareq Hassan Khan

  6. Department of Biological Sciences, Faculty of Agricultural Sciences, University of Ciego de Avila, 69450, Ciego de Avila, Cuba

    Gerardo M. Casañola-Martín

  7. The Norwegian Structural Biology Centre (NorStruct), University of Tromso, Tromso, 9037, Norway

    Arjumand Ather

  8. S. Yunusov Institute of Chemistry of Plant Substances, Academy of Sciences, Uzbekistan, Tashkent

    Mukhlis N. Sultankhodzhaev

  9. Advanced Medisyns, Inc., 601 Carlson Parkway, Suite 1050, Minnetonka, MN, 55305, USA

    Richard Rotondo

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  1. Yovani Marrero-Ponce
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Marrero-Ponce, Y., Khan, M.T.H., Casañola-Martín, G.M. et al. Bond-based 2D TOMOCOMD-CARDD approach for drug discovery: aiding decision-making in ‘in silico’ selection of new lead tyrosinase inhibitors. J Comput Aided Mol Des 21, 167–188 (2007). https://doi.org/10.1007/s10822-006-9094-7

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