The calculation of residue-level interaction energies reflects a similar trend. Even though a few neighbouring residues, such as Ile10, Val18, Glu81 and Asp86 have similar or marginally higher interaction with roscovitine, most of the other pocket residues contribute more toward Y-27632 dihydrochloride distributor N-acetyl interaction. Major contributor toward the larger binding strength of N-acetyl was Lys33, followed by hinge region residues Leu83/Cys83, His84/ Asp84, Gln85. The hydrophobic Phe80 and the CDK2/CDK5 variant residue Asp145/Asn144 also contribute more favourably toward the N-acetyl inhibitor. Consequently, the total interaction energy of N-acetyl with CDKs turns out to be much greater than roscovitine. The decomposition of total energy into electrostatic and van der Waal components indicates that N-acetyl fared over roscovitine through the electrostatic interaction. The six fold increase of electrostatic component for the former mainly stems from the polar interaction of its N-acetyl group with Lys33, Asp145/Asn144, which reside deep into the CDK binding pocket. Hence, the future strategy for designing more potent and specific CDK inhibitors might incorporate polar functional groups that can reach deep into the CDK binding pocket through a hydrophobic linker, such as the cyclobutyl ring here. Cis-substituted cyclobutyl-4-aminoimidazole inhibitors have been identified as novel CDK5 inhibitors that gave improved enzyme and cellular potency with many fold selectivity over CDK2. The molecular basis of higher potency and selectivity of this class of inhibitors over commercially available drugs is also unknown. Here we GANT61 Hedgehog inhibitor present atomic-level details of the interactions of some of these CDK-inhibitor complexes to understand these differences. Results suggest that the aminoimidazole inhibitors can reach deep into the substrate-binding pocket through the linker cyclobutyl group. Moreover, they involve in strong electrostatic interactions with CDK residues Lys33, Asp145/Asn144 that reside at the base of the cavity. The better selectivity of these inhibitors for CDK5 mainly stems from the variant residues Cys83, Asp84, Asn144, which modulate the interaction network by subtly restructuring the binding pocket and realigning the allosteric residues, Lys33, Lys89. This turns the CDK5 pocket more electropositive and smaller in volume for more favourable interactions with molecules carrying multiple electronegative sites. The results are validated by comparing the computed free energy of binding of the imidazole inhibitors to CDKs with the available experimental values. Moreover, the mode of binding of the commercially available drug, roscovitine to CDKs in the simulated complexes is also compared to the available crystal structure. An excellent match has been observed in both instances, which tempted us to conclude that the future strategy for designing more potent and specific CDK inhibitors could involve the incorporation of polar functional groups at the tip of the inhibitor molecules, which can go deep into the binding pocket through a hydrophobic linker. Epigenetic changes in cancer involve cooperation of multiple processes including covalent modification of histones, where histone acetylation and methylation are among the modifications shown to contribute to epigenetic reprogramming in cancer. Histone deacetylase inhibitors have antitumor potential and represent important therapeutic supplements in acute myeloid leukemia where the need for effective low toxic therapy in an elderly patient population is critical.