7-Hydroxy-3-prenylcoumarin

19053772

We screened 26 bisphosphonates against a farnesyl diphosphate synthase from Plasmodium vivax, finding a poor correlation between enzyme and cell growth inhibition (R2 = 0.06). To better predict cell activity data, we then used a combinatorial descriptor search in which pIC50(cell) = a pIC50(enzyme) + bB + cC + d, where B and C are descriptors (such as SlogP), and a—d are coefficients. R2 increased from 0.01 to 0.74 (for a leave-two-out test set of 26 predictions). The method was then further validated using data for nine other systems, including bacterial, viral, and mammalian cell systems. On average, experimental/predicted cell pIC50 correlations increased from R2 = 0.28 (for an enzyme-only test set) to 0.70 (for enzyme plus two descriptor test set predictions), while predictions based on scrambled cell activity had no predictive value (R2 = 0.13). These results are of interest since they represent a general way to predict cell from enzyme inhibition data, with in three cases, R2 values increasing from ∼0.02 to 0.72.

Bisphosphonate Inhibition of a Plasmodium Farnesyl Diphosphate Synthase and a General Method for Predicting Cell-Based Activity from Enzyme Data

Dushyant Mukkamala,†‡ Joo Hwan No,†‡ Lauren M. Cass,§ Ting-Kai Chang,∥ and Eric Oldfield*†∥

2009 Oct 21

30867893

Camptothecin (CPT), a natural product and its synthetic derivatives exert potent anticancer activity by selectively targeting DNA Topoisomerase I (Top1) enzyme. CPT and its clinically approved derivatives are used as Top1 poisons for cancer therapy suffer from many limitations related to stability and toxicity. In order to envisage structurally diverse novel chemical entity as Top1 poison with better efficacy, Ligand-based-pharmacophore model was developed using 3D QSAR pharmacophore generation (HypoGen algorithm) methodology in Discovery studio 4.1 clients. The chemical features of 29 CPT derivatives were taken as the training set. The selected pharmacophore model Hypo1 was further validated by 33 test set molecules and used as a query model for further screening of 1,087,724 drug-like molecules from ZINC databases. These molecules were subjected to several assessments such as Lipinski rule of 5, SMART filtration and activity filtration. The molecule obtained after filtration was further scrutinized by molecular docking analysis on the active site of Top1 crystal structure (PDB ID: 1T8I). Six potential inhibitory molecules have been selected by analyzing the binding interaction and Ligand-Pharmacophore mapping with the validated pharmacophore model. Toxicity assessment TOPKAT program provided three potential inhibitory ‘hit molecules’ ZINC68997780, ZINC15018994 and ZINC38550809. MD simulation of these three molecules proved that the ligand binding into the protein-DNA cleavage complex is stable and the protein-ligands conformation remains unchanged. These three hit molecules can be utilized for designing future class of potential topoisomerase I inhibitor.

Topoisomerase I, Camptothecin, Anticancer agent, Inhibitor, Pharmacophore, Virtual screening, ZINC database, Molecular dynamics, Toxicity, ADMET

Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential Topoisomerase I Inhibitors

Sourav Pal,a,b Vinay Kumar,a,c Biswajit Kundu,a Debomita Bhattacharya,a Nagothy Preethy,a,c Mamindla Prashanth Reddy,a,c and Arindam Talukdara,b,⁎

2019;