title: Investigating the binding preferences of small molecule inhibitors of human protein arginine methyltransferase 1 using molecular modelling.
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.
authors.affiliation: School of Chemistry and Chemical Engineering, Beifang University of Nationalities, Yinchuan, PR China; Department of Oral Biology and Biomedical Sciences, and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, PR China.
authors.forename: Jingyang
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Laughton
authors.affiliation: Department of Oral Biology and Biomedical Sciences, and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Lee Fah
authors.initials: LF
authors.lastname: Yap
authors.affiliation: Department of Oral Biology and Biomedical Sciences, and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Paterson
authors.affiliation: School of Pharmacy, Ningxia Medical University, Yinchuan, PR China. Electronic address: paxhw@yahoo.co.uk.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
mesh_terms: D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008745:Methylation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: Active Site Pressurisation; Binding mode; Homology modelling; Molecular dynamic simulation; PRMT1 inhibitors