title: CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators.
abstract: Aromatase, the enzyme responsible for estrogen biosynthesis, is an attractive target in the treatment of hormone-dependent breast cancer. In this manuscript, the structure-based drug design approach of sulfonanilide analogues as potential selective aromatase expression regulators (SAERs) is described. Receptor-independent CoMFA (Comparative Molecular Field Analysis) maps were employed for generating a pseudocavity for LeapFrog calculation. A robust model, using 45 and 10 molecules in the training and test sets, respectively, was developed producing statistically significant results with cross-validated and conventional correlation coefficients of 0.656 and 0.956, respectively. This model was used to predict the activity of newly proposed molecules as SAERs candidates being two magnitude orders more potent than the previously reported compounds. Also in the present study, the computational blind docking method using eHiTS is tested on molecules study group and COX-2 enzyme. Future perspectives of the method in the screening of SAERs candidates with no COX-2 inhibitory activity are discussed.
authors.affiliation: Grupo de Química Cuántica y Teórica, Universidad de Cartagena, Programa de Química, Facultad de Ciencias Exactas y Naturales, Campus De Zaragocilla, Cartagena, Colombia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gueto
authors.forename: Juan
authors.initials: J
authors.lastname: Torres
authors.forename: Ricardo
authors.initials: R
authors.lastname: Vivas-Reyes
mesh_terms: D000813:Anilides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003198:Computer Simulation; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016018:Least-Squares Analysis; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D013450:Sulfones; D001141:Aromatase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2