Abstract
G9a protein methyltransferase is a potential epigenetic drug target in different cancers and other disease conditions overexpressing the enzyme. G9a is responsible for the H3K9 dimethylation mark, which epigenetically regulates gene expression. Arg8 and Lys9 of the H3 substrate peptide are the two crucial residues for substrate-specific recognition and methylation. Several substrate competitive inhibitors are reported for the potent inhibition of G9a by incorporating lysine mimic groups in the inhibitor design. In this study, we explored the concept of arginine mimic strategy. The hydrophobic segment of the reported inhibitors BIX-01294 and UNC0638 was replaced by a guanidine moiety (side-chain moiety of arginine). The newly substituted guanidine moieties of the inhibitors were positioned similar to the Arg8 of the substrate peptide in molecular docking. Additionally, improved reactivity of the guanidine-substituted inhibitors was observed in density functional theory studies. Molecular dynamics, molecular mechanics Poisson–Boltzmann surface area binding free energy, linear interaction energy, and potential mean force calculated from steered molecular dynamics simulations of the newly designed analogues show enhanced conformational stability and improved H-bond potential and binding affinity toward the target G9a. Moreover, the presence of both lysine and arginine mimics together shows a drastic increase in the binding affinity of the inhibitor towards G9a. Hence, we propose incorporating a guanidine group to imitate the substrate arginine’s side chain in the inhibitor design to improve the potency of G9a inhibitors.
Highlights
Until the identification of chaetocin, analogues of the methyl donor SAM such as S-adenosyl homocysteine (SAH) and methylthio adenosine were used as inhibitors of methyl
The ligand rmsd of UNC0638 guanidine analogue fluctuates, suggesting that the active site’s ligand is flexible (Figure S2). These results suggest that G9a and the newly designed guanidine analogues form a stable complex during molecular dynamics (MD) simulations, similar to the original G9a inhibitors
One of the techniques used in computer-aided drug design is a structure-based drug design (SBDD)
Summary
G9a protein methyltransferase, known as EHMT2(euchromatin histone methyltransferase 2) and KMT1C (lysine methyltransferase 1C), is primarily responsible for the dimethylation of H3K9 and many other nonhistone substrates; the cofactor SAM (S-adenosyl methionine) acts as the methyl group donor (Figure 1A).[1,2] G9a regulates several biological processes such as DNA methylation,[2] chromatin remodeling, transcriptional regulation,[2] proliferation, differentiation, apoptosis, tumor cell movement,[3−6] and HIV latency.[7,8] Besides, G9a is involved in cellular reprogramming,[9] embryonic development,[10] prevention of cardiac hypertrophy,[11] occurrences of Alzheimer’s disease,[12] retinoic acid signaling,[13] repairing of damaged DNA,[14] intellectual and cognitive disturbances.[15]. Several substrate-competitive inhibitors of G9a are reported (Figure 1B), for cancer treatment. Since the exploration of protein lysine methyltransferases during the early 2000s, chaetocin and BIX-01294 were reported as inhibitors of SU(VAR)[3,4,5,6,7,8,9] and G9a.16. Until the identification of chaetocin, analogues of the methyl donor SAM (cofactor) such as S-adenosyl homocysteine (SAH) and methylthio adenosine were used as inhibitors of methyl- Since the exploration of protein lysine methyltransferases during the early 2000s, chaetocin and BIX-01294 were reported as inhibitors of SU(VAR)[3,4,5,6,7,8,9] and G9a.16 Until the identification of chaetocin, analogues of the methyl donor SAM (cofactor) such as S-adenosyl homocysteine (SAH) and methylthio adenosine were used as inhibitors of methyl-
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