title: Molecular modeling evaluation of non-steroidal aromatase inhibitors.
abstract: A recent discovery of aromatase crystal structure triggered the efforts to design novel aromatase inhibitors for breast cancer therapy. While correlating docking scores with inhibitory potencies of known ligands, feeble robustness of scoring functions toward prediction was observed. This prompted us to develop new prediction models using stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LIGANDFIT, and GLIDE). Quantitative structure-activity relationships were developed between the aromatase inhibitory activity (pIC(50) ) of flavonoid derivatives (n=39) and docking scores and docking descriptors. QSAR models have been validated internally [using leave-one-out cross-validated r(2)(cv) (LOO-Q2))] and externally to ensure the predictive capacity of the models. Model 2 [M2] developed using consensus of docking scores of scoring functions viz. ASP, potential of mean force and DOCK Score (r(2)(cv)=0.850, r(2) = 0.870, r(2)(pred) = 0.633, RMSE = 0.363 μm, r(2)(m(test)) =0.831, r(2)(m(overall)) =0.832) was found to be better in predicting aromatase inhibitory potency (pIC(50) ) compared to the Model 1 [M1] based on docking descriptors (r(2)(cv)= 0.848, r(2) = 0.825, r(2)(pred) =0.788, RMSE=0.421μm, r(2)(m(test)) =0.808, r(2)(m(overall)) =0.821). It has been observed that the natural flavonoids and their derivatives were less potent compared to these scaffolds with imidazolylmethyl substitution owing to the interaction of nitrogen atom of the imidazole ring toward the heme (Fe(3+) ) of the aromatase. Results confirm the potential of our methodology for the design of new potent non-steroidal aromatase inhibitors.
authors: Department of Pharmaceutical Chemistry, University Institute of Pharmaceutical Sciences and Centre of Advanced Study in Pharmaceutical Sciences, Panjab University, Chandigarh, India.
authors: Bheemanapalli Lakshmi
authors: BL
authors: Narayana
authors: Deb
authors: D
authors: Pran Kishore
authors: Chadrasekaran
authors: C
authors: Balakumar
authors: Kaki Venkata
authors: KV
authors: Rao
authors: Rajwinder
authors: R
authors: Kaur
authors: Akkinepally Raghuram
authors: AR
authors: Rao
authors: Javali Narashima
authors: JN
authors: Murthy
authors: Muttineni
authors: M
authors: Ravikumar
mesh_terms: D001141:Aromatase / Q000737:chemistry / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008954:Models, Biological; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D001141:Aromatase