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Comput Biol Chem. 2019 Sep 6;83:107104. doi: 10.1016/j.compbiolchem.2019.107104. [Epub ahead of print]

Anticancer SAR establishment and novel accruing signal transduction model of drug action using biscoumarin scaffold.

Author information

1
Department of Chemistry, Indian Institute of Technology Ropar, Punjab, 140001, India.
2
School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh, 175005, India.
3
Department of Chemistry, Punjab University, Chandigarh, 160014, India. Electronic address: navneetkaur@pu.ac.in.
4
School of Basic Sciences, Indian Institute of Technology Mandi, Himachal Pradesh, 175005, India. Electronic address: neha@iitmandi.ac.in.
5
Department of Chemistry, Indian Institute of Technology Ropar, Punjab, 140001, India. Electronic address: nsingh@iitrpr.ac.in.

Abstract

In this paper, we have established methylenebis (4-hydroxy-2H-chromen-2-one) as a promising anticancer scaffold with kinesin spindle protein (KSP) inhibitory activity under malignant condition. A series of biscoumarin derivatives (MN1 to MN30) with different substituent were synthesized, and their anticancer activity was explored. Six biscoumarin derivatives that were found active were further selected to formulate organic nanoparticles (ONPs). Anticancer activity of both the forms (viz conventional and ONPs) was compared. MN30 was found most potent whereby MN10 showed good anticancer activity in both, i.e., conventional and ONP form; the structural activity relationship (SAR) study has been established. Computational investigation revealed biscoumarin scaffold as a suitable pharmacophore to bind against KSP protein. Molecular dynamics simulation studies revealed protein-ligand stability and dynamic behavior of biscoumarin-KSP complex. Finally, accruing signal transduction model was formulated to explain the observed MTT trend of conventional and ONP form. The model seems useful towards solving population specific varied results of chemotherapeutic agents. According to the model, MN10 and MN30 derivatives have good pharmacodynamics inertia and therefore, both the molecules were able to provide dose-dependent cytotoxic results.

KEYWORDS:

Anticancer; Biscoumarin; Chemotherapeutic; Kinesin spindle protein; Pharmacodynamics inertia

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