A few inhibitors of histone deacetylases (HDACs) are already approved for treatment.Through computational chemistry, the project supplies new insight into this new class ofanti-cancer drugs.
While DNA (deoxyribonucleic acid) is the molecular basis of genetics, several gene expression changes occur which are not coded in the DNA sequence itself. These are termed epi-genetic changes. As several diseases, including a number of cancers, are linked to epi-genetic changes, vast academic and industrial efforts are directed towards drug candidates which may be able to inhibit specific epi-genetic changes. Using computational methods, the project focuses on histone acetylation, which is an important type of epi-genetic modifications.
Histone deacetylases (HDACs) are a family of enzymes that contribute to the regulation of DNA expression. Over-expression of certain HDACs has been observed in several types of cancer including gastric, prostate,colon, breast, and cervical cancer. A few HDAC inhibitors have been approved for treatment of various cancers.
In the project, in silico studies were carried out to evaluate the binding mode and affinity of a collection of known macrocyclic HDAC inhibitors and their analogues towards class I HDACs. One particularly interesting class of HDAC inhibitors is the macrocyclic peptides and depsi-peptides, which are highly potent and moderately selective, and can be found in nature. The studies in this project confirmed the higher potency of hydroxamate analogues in comparison with their norvaline counterparts, as well as the crucial role of an aspartate in achieving the optimal binding position. Furthermore, the unexpected interaction between aromatic side chains of the inhibitors and the catalytic zinc ion opened a new line of investigation for possible HDAC inhibitors.
Another part of the project focused at class III HDACs, also known as sirtuins. These are NAD+-dependent enzymes with homology to the silent information regulator 2 yeast enzymes. There are seven proteins in the sirtuin family and they all share a conserved 270 amino acid catalytic domain, with variable NandC-termini. These enzymes have been suggested as therapeutic targets for diabetes, cancer, neuro-degenerative diseases and inflammation.
Molecular Dynamics simulations of NADH inhibition of SIRT1, SIRT3, and SIRT5 showed that the addition of a single proton in the nicotinamide ring can induce an important conformational change on NADH, causing misalignment of the nicotinamide to the key residues in the C pocket and ultimately resulting in a significant loss of binding affinity. Further, a homology model of SIRT7 was generated. The model includes the secondary structure of both N- and C- termini. The catalytic domain depicts a Rossmann-fold and a Zn2+-binding domain. The termini show a well-defined a-helix organization, essential for the DNA binding. The model is further supported by phylogenetic and structural analyses.
Besides the actual findings, the project contributes to demonstrate that molecular modelling is quickly becoming a go-to approach for efficient, robust and less costly studies.
Chromatin organization