1. Elaborate ligand-based modeling reveal new submicromolar Rho kinase inhibitors
- Author
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Rand Shahin, Mutasem O. Taha, and Saja Alqtaishat
- Subjects
Models, Molecular ,Quantitative structure–activity relationship ,Loo ,Stereochemistry ,Protein Conformation ,Quantitative Structure-Activity Relationship ,Context (language use) ,Ligands ,Drug Discovery ,Ic50 values ,Humans ,Physical and Theoretical Chemistry ,Enzyme Inhibitors ,Rho-associated protein kinase ,rho-Associated Kinases ,Binding Sites ,Ligand ,Chemistry ,Computer Science Applications ,ROC Curve ,Cardiovascular Diseases ,Drug Design ,Linear Models ,Multiple linear regression analysis ,Pharmacophore ,Software ,Protein Binding - Abstract
Rho Kinase (ROCKII) has been recently implicated in several cardiovascular diseases prompting several attempts to discover and optimize new ROCKII inhibitors. Towards this end we explored the pharmacophoric space of 138 ROCKII inhibitors to identify high quality pharmacophores. The pharmacophoric models were subsequently allowed to compete within quantitative structure-activity relationship (QSAR) context. Genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing self-consistent QSAR of optimal predictive potential (r (77) = 0.84, F = 18.18, r (LOO) (2) = 0.639, r (PRESS) (2) against 19 external test inhibitors = 0.494). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within ROCKII binding pocket. Receiver operating characteristic (ROC) curve analyses established the validity of QSAR-selected pharmacophores. Moreover, the successful pharmacophores models were found to be comparable with crystallographically resolved ROCKII binding pocket. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds Eight submicromolar ROCKII inhibitors were identified. The most potent gave IC(50) values of 0.7 and 1.0 μM.
- Published
- 2011