Ligand- and structure-basedin silicostudies to identify kinesin spindle protein (KSP) inhibitors as potential anticancer agents

Abstract

Kinesin spindle protein (KSP) belongs to the kinesin superfamily of microtubule-based motor proteins. KSP is 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 through the generation of monoastral MT arrays 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 modelling, virtual database screening, molecular docking and molecular dynamics. Initially, the pharmacophore models were generated from the data-set of highly potent KSP inhibitors and the pharmacophore models were validated against in house test set ligands. The validated pharmacophore model was then taken for database screening (Maybridge and 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 ligand binding 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 potential hits and evaluated these experimentally using in vitro KSP ATPase inhibition assays.

Current Challenges in Delivery and Cytosolic Translocation of Therapeutic RNAs

“…Alnylam Pharmaceuticals has successfully completed a Phase 1 clinical trial with ALN-VSP LNPs to treat advanced cancer with hepatic metastasis [ 104 ]. ALN-VSP comprises two siRNAs that target VEGF, which is critical for the growth of new blood vessels [ 105 ], and kinesin spindle protein (KSP), involved in cell division [ 106 ]. Upon parenteral administration, ALN-VSP passively accumulates in the liver, where it mediates anticancer activity.…”

Design and synthesis of novel thiadiazole-thiazolone hybrids as potential inhibitors of the human mitotic kinesin Eg5

“…54 Several recent literature reports and patents in the field of pharmaceutical and medicinal chemistry demonstrated that this strategy is being adopted successfully in many drug discovery projects. 55 In light of the highly interesting literature reports with respect to the ongoing clinical evaluation of thiadiazole-based Eg5 inhibitors, and in continuation of our efforts to design and synthesize novel heterocyclic medicinal compounds, 25,[56][57][58] we herein report the synthesis, spectral characterization, and evaluation of novel thiadiazole-thiazolone (TDT) hybrid compounds as potential inhibitors of the MT-stimulated Eg5 ATPase. The molecular hybridization approach was employed for the design of novel Eg5 inhibitor core moiety (Fig.…”

Eg5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance

“…YL001 inhibits the ATPase activity of the motor, blocks cells in mitosis and reduced melanoma tumor growth by 60% and significantly prolongs median survival time by more than 50% in a xenograft mouse model. A limitation of the virtual screening strategy is that although it may lead to the identification of small molecules that fulfill all the features of a pharmacophore, resembling those of known inhibitors, they may not display similar inhibitory activities in enzymatic and cell based assays [146]. To date, none of the identified Eg5 inhibitors by virtual screening have entered clinical trials yet.…”