title: Dragon method for finding novel tyrosinase inhibitors: Biosilico identification and experimental in vitro assays.
abstract: QSAR (quantitative structure-activity relationship) studies of tyrosinase inhibitors employing Dragon descriptors and linear discriminant analysis (LDA) are presented here. A data set of 653 compounds, 245 with tyrosinase inhibitory activity and 408 having other clinical uses were used. The active data set was processed by k-means cluster analysis in order to design training and prediction series. Seven LDA-based QSAR models were obtained. The discriminant functions applied showed a globally good classification of 99.79% for the best model Class=-96.067+1.988 x 10(2)X0Av +9 1.907 BIC3 + 6.853 CIC1 in the training set. External validation processes to assess the robustness and predictive power of the obtained model were carried out. This external prediction set had an accuracy of 99.44%. After that, the developed models were used in ligand-based virtual screening of tyrosinase inhibitors from the literature and never considered in either training or predicting series. In this case, all screened chemicals were correctly classified by the LDA-based QSAR models. As a final point, these fitted models were used in the screening of new bipiperidine series as new tyrosinase inhibitors. These methods are an adequate alternative to the process of selection/identification of new bioactive compounds. The biosilico assays and in vitro results of inhibitory activity on mushroom tyrosinase showed good correspondence. It is important to stand out that compound BP4 (IC(50)=1.72 microM) showed higher activity in the inhibition against the enzyme than reference compound kojic acid (IC(50)=16.67 microM) and l-mimosine (IC(50)=3.68 microM). These results support the role of biosilico algorithm for the identification of new tyrosinase inhibitor compounds.
authors.affiliation: Unit of Computer-Aided Molecular Biosilico Discovery and Bioinformatic Research (CAMD-BIR Unit), Department of Pharmacy, Faculty of Chemistry-Pharmacy, Central University of Las Villas, Santa Clara, 54830 Villa Clara, Cuba.
authors.forename: Gerardo M
authors.initials: GM
authors.lastname: Casañola-Martín
authors.forename: Yovani
authors.initials: Y
authors.lastname: Marrero-Ponce
authors.forename: Mahmud Tareq Hassan
authors.initials: MT
authors.lastname: Khan
authors.forename: Arjumand
authors.initials: A
authors.lastname: Ather
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Khan
authors.forename: Francisco
authors.initials: F
authors.lastname: Torrens
authors.forename: Richard
authors.initials: R
authors.lastname: Rotondo
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D016208:Databases, Factual; D016002:Discriminant Analysis; D015195:Drug Design; D008024:Ligands; D010455:Peptides / Q000032:analysis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D012984:Software
chemical_list: D008024:Ligands; D010455:Peptides; D010880:Piperidines