Abstract
Golgi α-mannosidase II (GMII) is a glycoside hydrolase playing a crucial role in the N-glycosylation pathway. In various tumour cell lines, the distribution of N-linked sugars on the cell surface is modified and correlates with the progression of tumour metastasis. GMII therefore is a possible molecular target for anticancer agents. Here, we describe the identification of a non-competitive GMII inhibitor using computer-aided drug design methods including identification of a possible allosteric binding site, pharmacophore search and virtual screening.
Highlights
Selectins are carbohydrate-recognizing proteins and are essential for adhesion of metastasizing cancer cells [1]
The potential allosteric binding pocket of the Golgi α-mannosidase II (GMII) protein was identified by using the Site Finder application of MOE v2014.10 (Chemical Computing Group, Montreal, QC, Canada) [21], which uses a methodology based on so-called alpha spheres that are derived from the receptor atoms and describe the shape of the protein
The protein structure of Drosophila melanogaster GMII (dGMII) was analyzed to detect pockets that could be targeted by allosteric inhibitors
Summary
Selectins are carbohydrate-recognizing proteins and are essential for adhesion of metastasizing cancer cells [1]. Oncogenic cells often show an altered distribution of oligosaccharides on their cell surface. This modified distribution of carbohydrates is linked to disease progression, metastasis and poor clinical outcome. Golgi α-mannosidase II (GMII) is one of these possible targets, since it is a key enzyme in N-glycan processing. Its inhibition has been linked to an induced tumour repression [3]. The alkaloid swainsonine, a well-known inhibitor of GMII, has exhibited anti-tumour effects in certain colon, breast, or skin cancer types [2]. Due to the simultaneous inhibition of the structurally related lysosomal mannosidase, side effects restrict the clinical use of this potent inhibitor [4,5,6]. GMII belongs to the hydrolase family 38 [7] and catalyzes the cleavage of α-(1,6) and α-(1,3) glycosidic bonds between mannose residues in GlcNAcMan5GlcNAc2 (GlcNAc: N-acetyl-glucosamine; Man: mannose) resulting in the formation of GlcNAcMan3GlcNAc2 [5]
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