An in silico design of bioavailability for kinase inhibitors evaluating the mechanistic rationale in the CYP metabolism of erlotinib
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.
KeywordsCYP450 Kinase inhibitors Metabolomics Molecular docking MD simulations
We are thankful to Dr. Sreedhara Voleti and Dr. Ramesh Sistla for their valuable insights and timely guidance for this specific study especially with the Stardrop software. We are grateful to Sathya Sai Baba, the founder chancellor, SSSIHL for his constant support and inspiration. We are also indebted to the administration of SSSIHL and the Department of Mathematics and Computer Science, SSSIHL, for providing the computational facility.
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