Molecular Basis for the Enhanced CDK2 Inhibition by Artesunate: Superior Binding Affinity to the ATP-Catalytic Site

Authors

  • Mohammad Rizki Fadhil Pratama Pharmacy Department, Faculty of Pharmacy, Universitas Muhammadiyah Palangkaraya, Palangka Raya, Central Kalimantan, Indonesia http://orcid.org/0000-0002-0727-4392
  • Evi Mulyani Doctoral Program of Pharmacy, Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, Special Region of Yogyakarta, Indonesia Pharmacy Department, Faculty of Pharmacy, Universitas Muhammadiyah Palangkaraya, Palangka Raya, Central Kalimantan, Indonesia http://orcid.org/0000-0002-6533-1260
  • Suratno Suratno Doctoral Program of Pharmaceutical Sciences, School of PhD Studies, Semmelweis University, Budapest, Central Hungary, Hungary Pharmacy Department, Faculty of Pharmacy, Universitas Muhammadiyah Palangkaraya, Palangka Raya, Central Kalimantan, Indonesia http://orcid.org/0000-0003-1740-1460
  • Punet Kumar Department of Pharmaceutical Chemistry, Shri Gopichand College of Pharmacy, Baghpat, India http://orcid.org/0000-0001-6047-6615
  • Daryono Hadi Tjahjono Pharmacochemistry Department, School of Pharmacy, Institut Teknologi Bandung, Bandung, West Java, Indonesia http://orcid.org/0000-0002-9675-0134
  • Tutus Gusdinar Kartawinata Pharmacochemistry Department, School of Pharmacy, Institut Teknologi Bandung, Bandung, West Java, Indonesia http://orcid.org/0000-0002-2478-2022

DOI:

https://doi.org/10.20527/jps.v13i1.24555

Keywords:

Artemisinin, Anticancer Agent, ATP, Molecular Docking, 13-Gly-16-Gly Loop

Abstract

This study aimed to identify the most potent CDK2 inhibitor among seven artemisinin derivatives and, critically, to elucidate its binding mechanism and compare its affinity with that of the natural ligand, ATP. Molecular docking was performed using AutoDock 4.2.6 toward inactive and active forms of CDK2. Ligands were optimized using the Hartree-Fock method basis set 6-311G. Blind docking on the active form was used to determine the inhibition mechanism, employing the free energy of binding (ΔG) and dissociation constant (Ki) as affinity markers. Artesunate was the most potent derivative, exhibiting the highest affinity towards the active CDK2 form, with a ΔG of -11.7 kcal/mol and a Ki of 2.66 nM. Blind docking confirmed an ATP-competitive inhibition mechanism. Remarkably, Artesunate's Ki was significantly lower than that of ATP (8.73 nM). This enhanced affinity is attributed to specific interactions between the hemisuccinate side chain and the critical amino acid region, from 13-Gly to 16-Gly. Artesunate is suggested as a potent, ATP-competitive CDK2 inhibitor with an affinity exceeding that of ATP. These hypothesis-generating results suggest anticancer potential, yet require validation via MD or assays; limitations like scoring bias and protein flexibility necessitate cautious interpretation regarding the 13-Gly to 16-Gly target.

Author Biographies

Mohammad Rizki Fadhil Pratama, Pharmacy Department, Faculty of Pharmacy, Universitas Muhammadiyah Palangkaraya, Palangka Raya, Central Kalimantan, Indonesia

Assistant Professor of PharmacyUniversitas Muhammadiyah Palangkaraya

Evi Mulyani, Doctoral Program of Pharmacy, Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, Special Region of Yogyakarta, Indonesia Pharmacy Department, Faculty of Pharmacy, Universitas Muhammadiyah Palangkaraya, Palangka Raya, Central Kalimantan, Indonesia

Doctoral StudentUniversitas Ahmad DahlanAssistant Professor of PharmacyUniversitas Muhammadiyah Palangkaraya

Suratno Suratno, Doctoral Program of Pharmaceutical Sciences, School of PhD Studies, Semmelweis University, Budapest, Central Hungary, Hungary Pharmacy Department, Faculty of Pharmacy, Universitas Muhammadiyah Palangkaraya, Palangka Raya, Central Kalimantan, Indonesia

Doctoral StudentSemmelweis UniversityAssistant Professor of PharmacyUniversitas Muhammadiyah Palangkaraya

Punet Kumar, Department of Pharmaceutical Chemistry, Shri Gopichand College of Pharmacy, Baghpat, India

Assistant Professor of PharmacologyShri Gopichand College of Pharmacy

Daryono Hadi Tjahjono, Pharmacochemistry Department, School of Pharmacy, Institut Teknologi Bandung, Bandung, West Java, Indonesia

Professor of Medicinal ChemistryInstitut Teknologi Bandung

Tutus Gusdinar Kartawinata, Pharmacochemistry Department, School of Pharmacy, Institut Teknologi Bandung, Bandung, West Java, Indonesia

Professor of Medicinal ChemistryInstitut Teknologi Bandung

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Published

2026-03-31

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Vol. 13 No. 1 (2026): Jurnal Pharmascience

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Jurnal Pharmascience

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