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  2. Design, synthesis, molecular dynamics simulation, MM/GBSA studies and kinesin spindle protein inhibitory evaluation of some 4-aminoquinoline hybrids

Design, synthesis, molecular dynamics simulation, MM/GBSA studies and kinesin spindle protein inhibitory evaluation of some 4-aminoquinoline hybrids

  • Comput Biol Chem. 2023 Aug;105:107881. doi: 10.1016/j.compbiolchem.2023.107881.
Shriram D Ranade 1 Shankar G Alegaon 2 U Venkatasubramanian 3 A Soundarya Priya 3 Rohini S Kavalapure 1 Jagdish Chand 1 Sunil S Jalalpure 4 D Vinod 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, Karnataka, India.
  • 2 Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, Karnataka, India. Electronic address: sgalegaon@gmail.com.
  • 3 School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur 613401, India.
  • 4 Department of Pharmacognosy and Phytochemistry KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Belagavi 590010, Karnataka, India.
  • 5 Computational Drug Design Lab, Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore 632014, Tamil Nadu, India.
Abstract

The discovery of novel chemotherapeutic agents is always challenging for researchers in industry and academia. Among the recent promising Anticancer therapeutic targets, an important modulatory factor in mitosis is the expression of the Kinesin family motor protein (Eg5). In terms of chemotherapy treatment, mitosis has gained significant attention due to its role as one of the biological processes that can be intervened in it. This study was undertaken to design, synthesise and evaluation of 4-aminoquinoline hybrid compounds as potential Eg5 inhibitors. Based on data collected from Malachite green and steady state ATPase assays, it has been determined that compounds such as 6c, 6d, 6g, and 6h are sensitive to Eg5 inhibition. In special mention, compounds 4 and 6c showed promising inhibitory activity in Malachite green assay with IC50 values of 2.32 ± 0.23 µM and 1.97 ± 0.23 µM respectively. Compound 4 showed favourable inhibitory potential Steady state ATPase Assay with IC50 value of 5.39 ± 1.39 µM. We performed molecular docking, MM/GBSA calculations, and molecular dynamic simulations to evaluate the interactions between ligands and the binding site of the Kinesin spindle protein to evaluate the functional consequences of these interactions. As a result of these findings, it can be concluded that these 4-amioquinoline Schiff's base hybrids may prove to be promising candidates for development as novel inhibitors of Eg5. Further in-vivo research in this area is required.

Keywords

4-aminoquinoline; Eg5 inhibitor; MM/GBSA; Molecular docking; Molecular dynamics.

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