title: Novel Diketopiperazine Dihydroorotate Dehydrogenase Inhibitors Purified from Traditional Tibetan Animal Medicine Osteon Myospalacem Baileyi.
abstract: Traditional Tibetan medicine provides an abundant source of knowledge on human ailments and their treatment. As such, it is necessary to explore their active single compounds used to treat these ailments to discover lead compounds with good pharmacologic properties. In this present work, animal medicine, Osteon Myospalacem Baileyi extracts have been separated using a two-dimensional preparative chromatographic method to obtain single compounds with high purity as part of the following pharmacological research. Five high-purity cyclic dipeptides from chromatography work were studied for their dihydroorotate dehydrogenase inhibitory activity on recombinant human dihydroorotate dehydrogenase enzyme and compound Fr. 1-4 was found to contain satisfying inhibition activity. The molecular modeling study suggests that the active compound Fr. 1-4 may have a teriflunomide-like binding mode. Then, the energy decomposition study suggests that the hydrogen bond between Fr. 1-4 and Arg136 can improve the binding mode to indirectly increase the van der Waals binding energy. All the results above together come to the conclusion that the 2, 5-diketopiperazine structure group can interact with the polar residues well in the active pocket using electrostatic power. If some proper hydrophobic groups can be added to the sides of the 2, 5-diketopiperazine group, it is believed that better 2, 5-diketopiperazine dihydroorotate dehydrogenase inhibitors will be found in the future.
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.|University of Chinese Academy of Sciences, Beijing, 100039, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.|University of Chinese Academy of Sciences, Beijing, 100039, China.
authors.forename: Huaixiu
authors.initials: H
authors.lastname: Wen
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.
authors.forename: Ruitao
authors.initials: R
authors.lastname: Yu
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.
authors.forename: Zenggen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.|University of Chinese Academy of Sciences, Beijing, 100039, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.
authors.forename: Qilan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhao
authors.affiliation: University of Electronic Science and Technology of China, Chengdu, 611731, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.
authors.forename: Yanduo
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Key Laboratory of Tibetan Medicine Research, Northwest Plateau Institute of Biology, Chinese Academy of Sciences, Xining, 810001, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Mei
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000090722:Dihydroorotate Dehydrogenase; D054659:Diketopiperazines / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D006253:Haversian System / Q000737:chemistry*; D006801:Humans; D038861:Medicine, Tibetan Traditional / Q000379:methods*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012377:Rodentia; D013329:Structure-Activity Relationship
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D054659:Diketopiperazines; D004151:Dipeptides; D004791:Enzyme Inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors
keywords: Dihydroorotate dehydrogenase inhibitors; Osteon Myospalacem Baileyi; Tibetan medicine; cyclic dipeptides; two-dimensional chromatography