Three-in-one agonists for PPAR-α, PPAR-γ, and PPAR-δ from traditional Chinese medicine

Abstract

Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-α, PPAR-γ, and PPAR-δ, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR-ligand complexes in a dynamic state. (S)-Tryptophan-betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-α, with Thr252, Thr253 and Lys331 of PPAR-δ, and with Arg316 and Glu371 of PPAR-γ. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome.

Evaluation of Correlation of Cell Cycle Proteins and Ki-67 Interaction in Paranasal Sinus Inverted Papilloma Prognosis and Squamous Cell Carcinoma Transformation

“…The bladder, renal pelvis, ureter, urethra, nose, and paranasal sinuses are all possible areas for IP occurrence [1]. Epistaxis and nasal obstruction with facial pain or headache attacked when the nose or sinuses mucosa bear the IP [2]. Although the IP originating from the outlining respiratory membrane belongs to a benign epithelial neoplasm, the local invasiveness, higher recurrence rate, and malignant transformation make it difficult to treat [3].…”

Computational Design of Apolipoprotein E4 Inhibitors for Alzheimer’s Disease Therapy from Traditional Chinese Medicine

“…The data shows that Glu77 is a crucial residue for Budmunchiamine L5 binding. We also employed CAVER 3.0 software [71] to analyze the migrated ligand tunnels in ApoE4 (Figure 11), and the ligand pathway analysis was used to predict in previous studies [40]. The prediction of ApoE4 showed lower number of channels than Apo form of ApoE4; the results illustrated that the TCM candidates could form stable binding conformation to interact with ApoE4 with all simulation time.…”

“…CADD is an efficient approach for the rapid identification of potential lead compounds in target therapy [20, 21] and has been widely used in drug design including virus therapy [22–26], cancer therapy [27–31], treatment of sleeplessness [32], neuropathic therapy [33–38], weight loss therapy [39, 40], diabetic treatment [41], inflammation treatment [42], erectile dysfunction treatment [43], and hair loss therapy [44]. For target proteins, drug design should depend on some illness research [25, 41, 45–49], risk-factor studies [50–53], web server [23, 54], and scientific theories [55]; mutant proteins are also important factors as drug targets [56].…”

Potential Retinoid X Receptor Agonists for Treating Alzheimer’s Disease from Traditional Chinese Medicine

“…Previously to in silico drug discovery researches, many compounds extracted from traditional Chinese medicine (TCM) have been indicated as potential lead compounds used for wide range of diseases, including metabolic syndrome [34–36], stroke [37–40], cancers [41–45], influenza [46–49], viral infection [50], diabetes [51], inflammation [52], and some other diseases [53, 54]. To improve drug discovery from TCM compounds, we aim to investigate the potent candidates as RXR agonists from the vast repertoire of TCM compounds in TCM Database@Taiwan.…”