ABSTRACT
Soft spot analysis helps evaluate the site of the metabolic lability that impacts the bio-availability of the drug. However, given its laborious and time consuming experimentation, we propose a reliable and cheap in silico strategy. In this context, we hypothesized a mechanistic rationale for metabolism of erlotinib by the CYP3A4 enzyme. The comparison of the 3D conformations of the target CYP class of enzymes using MD simulations with GROMACS helped evaluate its impact on the metabolism. The molecular docking studies using Autodock-Vina ascertained the explicit role of the Fe ion present in the Heme moiety in this process. This mechanism was confirmed with respect to 13 other popular approved FDA kinase inhibitors using ab initio DFT calculations using Gaussian 09 (G09), molecular docking studies with Autodock-Vina, and MD simulations with GROMACS. We then developed a quantitative (Q-Met) metabolic profile of these soft spots in the molecules and demonstrated the lack of a linear relationship between the extent of metabolism and drug efficacy. We thus propose an economic in silico strategy for the early prediction of the lability in kinase inhibitors to help model their bio-availability and activity simultaneously, prior to clinical testing.
Subject(s)
Cytochrome P-450 CYP3A/chemistry , Erlotinib Hydrochloride/pharmacokinetics , Protein Kinase Inhibitors/chemistry , Binding Sites , Biological Availability , Computer Simulation , Cytochrome P-450 CYP3A/metabolism , Drug Design , Erlotinib Hydrochloride/chemistry , Erlotinib Hydrochloride/metabolism , Humans , Models, Molecular , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , ThermodynamicsABSTRACT
A one-pot, cost-effective system for sensing fluoride ions using quinizarin as a novel chromophore is reported. Quinizarin complexes with Al(III) to form a self-organized turn-on fluorescence system in methanol. In the presence of fluoride ions, this system undergoes a subsequent ligand swap reaction with the fluoride ion and consequently the fluorescence turns off, delivering a sensitive route for the estimation of fluoride. This domino effect presents a sensitive and selective reaction system for the detection of fluoride ions in the concentration range 0.5-15 ppm. The study was performed using spectrophotometric and spectrofluorimetric techniques. Various analytical parameters such as pH, equilibration time, ambient temperature, and applicability of the method have been reported along with the study of the associated interfering ions.
