An assessment of crucial structural contributors of HDAC6 inhibitors through fragment-based non-linear pattern recognition and molecular dynamics simulation approaches

Amidst the Zn2+-dependant isoforms of the HDAC family, the HDAC6 has emerged as a potential target associated with an array of diseases, especially cancer and neuronal disorders like Rett’s Syndrome, Alzheimer’s disease, Huntington’s disease, etc. Also, despite the availability of a handful of HDAC inhibitors in the market, their non-selective nature has restricted their use in different disease conditions. In this situation, the development of selective and potent HDAC6 inhibitors will provide efficacious therapeutic agents to treat different diseases. In this context, this study has been carried out to evaluate the potential structural contributors of quinazoline-cap-containing HDAC6 inhibitors via machine learning (ML), conventional classification-dependant QSAR, and MD simulation-based binding mode of interaction analysis toward HDAC6 binding. This combined conventional and modern molecular modeling study has revealed the significance of the quinazoline moiety, substitutions present at the quinazoline cap group, as well as the importance of molecular property, number of hydrogen bond donor-acceptor functions, carbon-chlorine distance that significantly affects the HDAC6 binding of these inhibitors as well as their potency against HDAC6. Interestingly, the study also revealed that the substitutions such as the chloroethyl group, and bulky quinazolinyl cap group can affect the binding of the cap function with the amino acid residues present in the loops proximal to the catalytic site of HDAC6. Such contributions of cap groups can lead to both stabilization and destabilization of the cap function after occupying the hydrophobic catalytic site occupied by the aryl hydroxamate linker-ZBG functions.