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Targeting the Autophagy Specific Lipid Kinase VPS34 for Cancer Treatment: An Integrative Repurposing Strategy

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Abstract

The impact of autophagy on cancer treatment and its corresponding responsiveness has galvanized the scientific community to develop novel inhibitors for cancer treatment. Importantly, the discovery of inhibitors that targets the early phase of autophagy was identified as a beneficial choice. Despite the number of research in recent years, screening of the DrugBank repository (9591 molecules) for the Vacuolar protein sorting 34 (VPS34) has not been reported earlier. Therefore, the present study was designed to identify potential VPS34 antagonists using integrated pharmacophore strategies. Primarily, an energy-based pharmacophore and receptor cavity-based analysis yielded five (DHRRR) and seven featured (AADDHRR) pharmacophore hypotheses respectively, which were utilized for the database screening process. The glide score, the binding free energy, pharmacokinetics and pharmacodynamics properties were examined to narrow down the screened compounds. This analysis yielded a hit molecule, DB03916 that exhibited a better docking score, higher binding affinity and better drug-like properties in contrast to the reference compound that suffers from a toxicity property. Importantly, the result was validated using a 50 ns molecular dynamics simulation study. Overall, we conclude that the identified hit molecule DB03916 is believed to serve as a prospective antagonist against VPS34 for cancer treatment.

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Acknowledgments

K.V and T.R of the manuscript would like to thank the management of Chulalongkorn University (CU) for providing the facility and support to carry out this work. K.V would also like to thank Ratchadapisek Somphot Fund for the postdoctoral fellowship and the Structural and Computational Biology Research Unit, Faculty of Science, CU, for facility and computing resources.

Funding

The authors P.Mu and R.K thank VIT for providing ‘VIT SEED GRANT’ for carrying out this research work.

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Authors and Affiliations

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

    Poornimaa Murali & Ramanathan Karuppasamy

  2. Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Bangkok, 10330, Thailand

    Kanika Verma & Thanyada Rungrotmongkol

  3. Department of Chemical Engineering, AC Tech Campus, Anna University, Chennai, Tamil Nadu, 600025, India

    Perarasu Thangavelu

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  1. Poornimaa Murali
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  2. Kanika Verma
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Correspondence to Ramanathan Karuppasamy.

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Murali, P., Verma, K., Rungrotmongkol, T. et al. Targeting the Autophagy Specific Lipid Kinase VPS34 for Cancer Treatment: An Integrative Repurposing Strategy. Protein J 40, 41–53 (2021). https://doi.org/10.1007/s10930-020-09955-4

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