The hunt for antimitotic agents: an overview of structure-based design strategies

ABSTRACT

Introduction: Structure-based drug discovery offers a rational approach for the design and development of novel anti-mitotic agents which target specific proteins involved in mitosis. This strategy has paved the way for development of a new generation of chemotypes which selectively interfere with the target proteins. The interference of these anti-mitotic targets implicated in diverse stages of mitotic cell cycle progression culminates in cancer cell apoptosis.

Areas covered: This review covers the various mitotic inhibitors developed against validated mitotic checkpoint protein targets using structure-based design and optimization strategies. The protein-ligand interactions and the insights gained from these studies, culminating in the development of more potent and selective inhibitors, have been presented.

Expert opinion: The advent of structure-based drug design coupled with advances in X-ray crystallography has revolutionized the discovery of candidate lead molecules. The structural insights gleaned from the co-complex protein-drug interactions have provided a new dimension in the design of anti-mitotic molecules to develop drugs with a higher selectivity and specificity profile. Targeting non-catalytic domains has provided an alternate approach to address cross-reactivity and broad selectivity among kinase inhibitors. The elucidation of structures of emerging mitotic drug targets has opened avenues for the design of inhibitors that target cancer.

KEYWORDS:

• Antimitotic
• cancer therapy
• kinase inhibitor
• mitotic checkpoints
• structure-based drug design

Article highlights

• Structure based drug design (SBDD) of antimitotic inhibitor has successfully generated a plethora of potential inhibitors capable of circumventing mitotic drug targets.

• SBDD can effectively be employed to improve the potency of existing class of inhibitor by optimization and de novo design strategies.

• Structure guided approach is capable of addressing cross-reactivity and broad selectivity among kinase inhibitors. Selectivity is tweaked by exploiting key differences at the binding sites.

• Optional strategies have been employed to deal with cross-reactivity like designing inhibitors against an additional essential non-catalytic domain of the enzyme.

• Bolstering antimitotic interventions necessitates recognition of novel targets involved in oncogeneic progression and subsequent identification of inhibitors using rational structure guided approaches.

• Mode of therapy utilizing combinatorial strategy is recommended over monotherapy with combined inhibitors targeting multiple targets.

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Declaration of interest

P Kaur is in receipt of Indian Council of Medical Research grant support (grant no: BIC/12(04)/2013. D Dube is supported by a fellowship from the Council of Scientific and Industrial Research. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.