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Density Functional Theory and Molecular Simulation Studies for Prioritizing Anaplastic Lymphoma Kinase Inhibitors

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Abstract

Targeting anaplastic lymphoma kinase (ALK) is one of the important treatment strategies for the treatment of non-small cell lung cancer (NSCLC). In the present perspective, multidimensional approaches were used for the identification of ALK inhibitors. Initially, an e-pharmacophore model was generated using the PHASE algorithm and was used as a 3D query to screen 468,200 molecules of ASINEX database. Prior to the screening process, the model was evaluated for its significance and the ability to differentiate actives from inactives, using enrichment analysis. Subsequently, the hierarchical docking protocol and binding free energy calculations were instigated using GLIDE algorithm and Prime module, respectively. Further, the pharmacokinetic/pharmacodynamics (PK/PD) properties and toxicities of the hit compounds were envisaged respectively using QikProp program, Osiris explorer, and Protox-II algorithm. These approaches retrieved two hits namely BAS 00137817 and BAS 00680055 with acceptable absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and higher affinity towards ALK protein. Additionally, density functional theory calculations and molecular dynamics simulations were performed to validate the inhibitory activity of the lead compounds. It is noteworthy to mention that all the hits constitute of particular scaffolds which play a major role in the downregulation of some ALK-positive lung cancer pathways. We speculate that the outcomes of this research are of substantial prominence in the rational designing of novel and efficacious ALK inhibitors.

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Acknowledgments

The authors are grateful to the Department of Science and Technology-Science and Engineering Research Board (DST-SERB) for funding the research project (File No. EMR/2016/001675) and the management of VIT University, Vellore, for providing the facilities to carry out this work. KR thank ICMR for their support by the International Fellowship for Young Biomedical Scientists Award. VS acknowledges support from Bioinformatics Resources and Applications Facility (BRAF), C-DAC, Pune.

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  1. Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India

    Nivya James, V. Shanthi & K. Ramanathan

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  1. Nivya James
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James, N., Shanthi, V. & Ramanathan, K. Density Functional Theory and Molecular Simulation Studies for Prioritizing Anaplastic Lymphoma Kinase Inhibitors. Appl Biochem Biotechnol 190, 1127–1146 (2020). https://doi.org/10.1007/s12010-019-03156-1

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