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Ligand and structure based in silico studies to identify kinesin spindle protein (KSP) inhibitors as potential anticancer agents

Balakumar, C; Ramesh, M; Tham, CL; Khathi, SP; Kozielski, F; Srinivasulu, C; Hampannavar, GA; ... Karpoormath, R; + view all (2017) Ligand and structure based in silico studies to identify kinesin spindle protein (KSP) inhibitors as potential anticancer agents. Journal of Biomolecular Structure and Dynamics 10.1080/07391102.2017.1396255. (In press). Green open access

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Abstract

Kinesin spindle protein (KSP) belongs to the kinesin superfamily of microtubule-based motor proteins. KSPis responsible for the establishment of the bipolar mitotic spindle which mediates cell division. Inhibition of KSP expedites the blockade of the normal cell cycle during mitosis throughthe generation of monoastralMTarrays that finally cause apoptotic cell death. As KSP is highly expressed in proliferating/cancer cells, it has gained considerable attention as a potential drug target for cancer chemotherapy. Therefore, this study envisaged to design novel KSP inhibitors by employing computational techniques/tools such as pharmacophore modeling, virtual database screening, molecular docking, and molecular dynamics. Initially, the pharmacophore models were generated from the dataset of highly potent KSP inhibitors and the pharmacophore models were validated against in housetest set ligands.The validated pharmacophore model was then taken for database screening (Maybridgeand ChemBridge) to yield hits, which were further filtered for their drug-likeliness. The potential hits retrieved from virtual database screening were docked using CDOCKER to identify the ligandbinding landscape. The top-ranked hits obtained from molecular docking were progressed to molecular dynamics (AMBER) simulations to deduce the ligand binding affinity. This study identified MB-41570 and CB-10358 as potentialhits and evaluated experimentally using in vitroKSP ATPase inhibition assays.

Type: Article
Title: Ligand and structure based in silico studies to identify kinesin spindle protein (KSP) inhibitors as potential anticancer agents
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1080/07391102.2017.1396255
Publisher version: http://dx.doi.org/10.1080/07391102.2017.1396255
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: CDOCKER, KSP ATPase enzyme inhibition, KSP inhibitors, molecular dynamics, pharmacophore modeling
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > SoP Pharmaceutical and Bio Chemistry
URI: http://discovery.ucl.ac.uk/id/eprint/10033878
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