Inhibitors of histone deacetylase superfamily (HDAC), which induce cell cycle arrest, trigger cell death and reduce angiogenesis appear as promising anti-cancer drugs targeting the epigenetic regulation of gene expression. Approved HDAC inhibitors were found effective against haematological and solid malignancies, other HDACIs are currently in clinical trials for the treatment of neurological diseases or immune disorders. Among those, diarylcyclopropane hydroxamic acids (DCHA) were found to be potent and selective inhibitors of the class IIa HDACs, specifically HDAC4, a pharmacological target for the treatment of Huntington's disease and muscular atrophy. Crystallographic analysis revealed that one of the aryl groups of the DCHA fills the lower specificity pocket of the HDAC4 catalytic site that is specific for the class IIa HDACs. We have used computer-assisted combinatorial chemistry, hybrid quantum mechanics/molecular mechanics (QM/MM) with implicit solvation and QSAR models to optimize DCHA inhibitors and propose more potent DCHA analogues. The QM/MM approach has been selected since the process of inhibitor binding to the catalytic zinc and polar amino acid residues of the deacetylase active site induces considerable rearrangement of electron density of the inhibitor. Virtual combinatorial library consisting of 12180 DCHA analogues was focused by means of structure-based evaluation to form a small combinatorial subset enriched in potentially interesting inhibitor candidates. Two validated QSAR models making use of computed relative binding affinities of the DCHA inhibitors to the HDAC4 (ΔΔGcomQM/MM) were utilized to estimate the inhibitory potencies of the new analogues. The predicted half-maximal inhibitory concentrations (IC50pre) of the designed analogues fall into the low nanomolar concentration range and their predicted ADME properties are also favourable. The best designed DCHA analogues contain indazole, phenylpiperidine, phenyloxazole or hydroxypyridine moieties and stabilize bound inhibitors by hydrogen bonds to the catalytic water molecule and backbone carbonyl groups of the deacetylase active site residues. This makes them more potent and more specific inhibitors towards the HDAC4 isoform than the known diarylcyclopropane hydroxamic acids. The analogues are recommended for synthesis and experimental verification of inhibitory potencies in medicinal chemistry laboratories.