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Combination therapies that include treatment of cancerous cells with histone deacetylase (HDACs) inhibitors prior to treatment with topoisomerase inhibitors have shown synergistic anti-tumor effects. The promising results of such combination therapies have led to the development of a novel class of multitarget hybrid inhibitors that are designed by merging the scaffolds of topoisomerase and HDAC inhibitors, which consequently inhibit both classes of cancer-inducing targets simultaneously. These multitarget hybrids also have pharmacokinetic advantages over the traditional combinatorial approach, which struggles with disadvantages like maintaining optimum concentrations of multiple toxic drugs, which in turn leads to enhanced toxicity and other side-effects associated with the multiple drugs administered. Binding modes of some Top-HDAC hybrids have been predicted with the help of molecular docking in order to understand the binding of such hybrids with their target receptors and to identify the structural determinants responsible for their synergistic anti-tumor effect. Extra precision docking of Top1-HDAC and Top2-HDAC hybrid inhibitors has been carried out with Top1-DNA, Top2-DNA, HDAC1 and HDAC6 receptor structures. A detailed analysis of the molecular interactions of the hybrids with the target receptor binding sites has been undertaken and their predicted binding modes have been compared with the crystal binding modes of their component drugs. An explanation for the apparent selectivity of the hybrids towards HDAC6 has also been provided.

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