Computational Drug Repurposing of a Ketamine–Methylphenidate Conjugate for Targeting GLIPR1 in Human Glioma: Computational Targeting of GLIPR1 Using a Ketamine–Methylphenidate Conjugate

Muzamal Hussain; Saad Karim Abbasi; Faiz Ahmad Joyia; Moin Sajjad; Noor Ul Eman; Kashaf Shafique; Nazia Kanwal; Kashif Iqbal

doi:10.54393/fbt.v5i4.220

Authors

Muzamal Hussain Institute of Physiology and Pharmacology, Faculty of Veterinary Science, University of Agriculture Faisalabad, Faisalabad, Punjab, Pakistan
Saad Karim Abbasi Institute of Microbiology, Faculty of Veterinary Science, The University of Agriculture, Faisalabad, Punjab, Pakistan
Faiz Ahmad Joyia Centre of Agricultural Biochemistry and Biotechnology, The University of Agriculture, Faisalabad, Punjab, Pakistan
Moin Sajjad Department of Biological Sciences, Faculty of Sciences, The Superior University, Lahore, Punjab, Pakistan
Noor Ul Eman Department of Biochemistry, The University of Agriculture, Faisalabad, Punjab, Pakistan
Kashaf Shafique Institute of Physiology and Pharmacology, Faculty of Veterinary Science, University of Agriculture Faisalabad, Faisalabad, Punjab, Pakistan
Nazia Kanwal Department of Biological Sciences, Faculty of Sciences, The Superior University, Lahore, Punjab, Pakistan
Kashif Iqbal Institute of Physiology and Pharmacology, Faculty of Veterinary Science, University of Agriculture Faisalabad, Faisalabad, Punjab, Pakistan

DOI:

https://doi.org/10.54393/fbt.v5i4.220

Keywords:

Glioma, Ketamine, Methylphenidate, Conjugate, Docking, Tumor, Brain

Abstract

Gliomas are the most aggressive primary brain tumors, characterized by high mortality, therapeutic resistance, and limited treatment options due to blood–brain barrier constraints. Glioma pathogenesis-related protein 1 (GLIPR1) is highly upregulated in malignant gliomas and minimally expressed in normal brain tissue, making it a promising molecular target. Drug conjugation strategies may improve CNS delivery and therapeutic efficiency against such targets. Objectives: This study aimed to investigate the binding potential and pharmacokinetic feasibility of a ketamine–methylphenidate conjugate against the glioma-associated protein GLIPR1 using in silico approaches. Methodology: The three-dimensional structure of GLIPR1 (PDB ID: 3Q2U) was retrieved and prepared using Discovery Studio. Structural validation was performed through Ramachandran plot analysis, SOPMA, and PROCHECK. Active site prediction was carried out using PrankWeb, and physicochemical properties were assessed with ProtParam. The ketamine–methylphenidate conjugate (SDF format) was obtained from Nouman Ali et al. and evaluated for ADMET properties using pkCSM. Molecular docking was performed using CB-Dock, and ligand–protein interactions were analyzed via Discovery Studio. Results: Docking analysis revealed a favorable binding affinity (−6.9 kcal/mol), supported by two hydrogen bonds, five hydrophobic interactions, and one electrostatic interaction. Pharmacokinetic profiling indicated suitable absorption, moderate BBB permeability, and an acceptable safety profile, supporting CNS applicability. Conclusions: The findings suggest that the ketamine–methylphenidate conjugate is a promising CNS-penetrant candidate with potential relevance in glioma management, warranting further experimental validation.

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