Computational Approaches to the Rational Design of Tubulin-Targeting Agents

Abstract

Microtubules are highly dynamic polymers of α,β-tubulin dimers which play an essential role in numerous cellular processes such as cell proliferation and intracellular transport, making them an attractive target for cancer and neurodegeneration research. To date, a large number of known tubulin binders were derived from natural products, while only one was developed by rational structure-based drug design. Several of these tubulin binders show promising in vitro profiles while presenting unacceptable off-target effects when tested in patients. Therefore, there is a continuing demand for the discovery of safer and more efficient tubulin-targeting agents. Since tubulin structural data is readily available, the employment of computer-aided design techniques can be a key element to focus on the relevant chemical space and guide the design process. Due to the high diversity and quantity of structural data available, we compiled here a guide to the accessible tubulin-ligand structures. Furthermore, we review different ligand and structure-based methods recently used for the successful selection and design of new tubulin-targeting agents.

Identifying and characterising promising small molecule inhibitors of kinesin spindle protein using ligand-based virtual screening, molecular docking, molecular dynamics and MM‑GBSA calculations

“…Kinesins also called ‘‘ nanomotors”, because they generate energy from ATP hydrolysis and use it in the transport and movement of the intracellular cargos along the spindle microtubules (MTs) [ 2 ]. Eg5, also known as KIF11, is a member of the kinesins superfamily, particularly the mitotic kinesin-5 subgroup [ 3 ]. Eg5 is a homotetrameric motor protein that plays an important role in early mitosis through separation of the duplicated centrosomes, bipolar spindle formation, alignment and segregation of the chromosomes [ 4 ].…”

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