Computational Investigation of a Series of Small Molecules as Potential Compounds for Lysyl Hydroxylase-2 (LH2) Inhibition.

Autor:	Maghsoud Y; Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States., Vázquez-Montelongo EA; Department of Physical Medicine and Rehabilitation, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States., Yang X; Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States., Liu C; Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States., Jing Z; Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States., Lee J; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, United States., Harger M; Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States., Smith AK; Department of Chemistry, University of North Texas, Denton, Texas 76201, United States., Espinoza M; Department of Chemistry, University of North Texas, Denton, Texas 76201, United States., Guo HF; Department of Molecular and Cellular Biochemistry, College of Medicine, The University of Kentucky, Lexington, Kentucky 40536, United States., Kurie JM; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77005, United States., Dalby KN; Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, United States., Ren P; Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, United States., Cisneros GA; Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States.; Department of Physics, The University of Texas at Dallas, Richardson, Texas 75080, United States.
Jazyk:	angličtina
Zdroj:	Journal of chemical information and modeling [J Chem Inf Model] 2023 Feb 13; Vol. 63 (3), pp. 986-1001. Date of Electronic Publication: 2023 Jan 30.
DOI:	10.1021/acs.jcim.2c01448
Abstrakt:	The catalytic function of lysyl hydroxylase-2 (LH2), a member of the Fe(II)/αKG-dependent oxygenase superfamily, is to catalyze the hydroxylation of lysine to hydroxylysine in collagen, resulting in stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs). Reports show that high amounts of LH2 lead to the accumulation of HLCCs, causing fibrosis and specific types of cancer metastasis. Some members of the Fe(II)/αKG-dependent family have also been reported to have intramolecular O 2 tunnels, which aid in transporting one of the required cosubstrates into the active site. While LH2 can be a promising target to combat these diseases, efficacious inhibitors are still lacking. We have used computational simulations to investigate a series of 44 small molecules as lead compounds for LH2 inhibition. Tunneling analyses indicate the existence of several intramolecular tunnels. The lengths of the calculated O 2 -transporting tunnels in holoenzymes are relatively longer than those in the apoenzyme, suggesting that the ligands may affect the enzyme's structure and possibly block (at least partially) the tunnels. The sequence alignment analysis between LH enzymes from different organisms shows that all of the amino acid residues with the highest occurrence rate in the oxygen tunnels are conserved. Our results suggest that the enolate form of diketone compounds establishes stronger interactions with the Fe(II) in the active site. Branching the enolate compounds with functional groups such as phenyl and pyridinyl enhances the interaction with various residues around the active site. Our results provide information about possible leads for further LH2 inhibition design and development.
Databáze:	MEDLINE
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