Investigating the binding preferences of small molecule inhibitors of human protein arginine methyltransferase 1 using molecular modelling

Hong, Wei; Laughton, Charles A.; Li, Jingyang; Yap, Lee Fah; Paterson, Ian C.; Wang, Hao

Abstract

Protein arginine methyltransferases (PRMTs) catalyse the methylation of arginine residues of target proteins. PRMTs utilise S-adenosyl methionine (SAM) as the methyl group donor, leading to S-adenosyl homocysteine (SAH) and monomethylarginine (mMA). A combination of homology modelling, molecular docking, Active Site Pressurisation, molecular dynamic simulations and MM-PBSA free energy calculations is used to investigate the binding poses of three PRMT1 inhibitors (ligands 1–3), which target both SAM and substrate arginine binding sites by containing a guanidine group joined by short linkers with the SAM derivative. It was assumed initially that the adenine moieties of the inhibitors would bind in sub-site 1 (PHE44, GLU137, VAL136 and GLU108), the guanidine side chain would occupy sub-site 2 (GLU 161, TYR160, TYR156 and TRP302), with the amino acid side chain occupying sub-site 3 (GLU152, ARG62, GLY86 and ASP84; pose 1). However, the SAH homocysteine moiety does not fully occupy sub-site 3, suggesting another binding pose may exist (pose 2), whereby the adenine moiety binds in sub-site 1, the guanidine side chain occupies sub-site 3, and the amino acid side chain occupies sub-site 2. Our results indicate that ligand 1 (pose 1 or 2), ligand 2 (pose 2) and ligand 3 (pose 1) are the predominant binding poses and we demonstrate for the first time that sub-site 3 contains a large space that could be exploited in the future to develop novel inhibitors with higher binding affinities.

Citation

Hong, W., Laughton, C. A., Li, J., Yap, L. F., Paterson, I. C., & Wang, H. (2014). Investigating the binding preferences of small molecule inhibitors of human protein arginine methyltransferase 1 using molecular modelling. Journal of Molecular Graphics and Modelling, 51, 193-202. https://doi.org/10.1016/j.jmgm.2014.05.010

• Journal Article Type: Article
• Acceptance Date: May 28, 2014
• Online Publication Date: Jun 4, 2014
• Publication Date: 2014-06
• Deposit Date: Dec 20, 2017
• Journal: Journal of Molecular Graphics and Modelling
• Print ISSN: 1093-3263
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 51
• Pages: 193-202
• DOI: https://doi.org/10.1016/j.jmgm.2014.05.010
• Keywords: PRMT1 inhibitors; Homology modelling; Active Site Pressurisation; Molecular dynamic simulation; Binding mode
• Public URL: https://nottingham-repository.worktribe.com/output/1110251
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1093326314000837?via%3Dihub