Biomedical subjects
Publications and source records attributed to Minmin Wang.
PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
The design of a novel selective estrogen receptor modulator (SERM) for the potential treatment of uterine leiomyoma is described. 16 (LY2066948-HCl) binds with high affinity to estrogen receptors alpha and beta (ERalpha and ERbeta, respectively) and is a potent uterine antagonist with minimal effects on the ovaries as determined by serum biomarkers and histologic evaluation.
To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.
[reaction: see text] We have previously described a model of paclitaxel-microtubule binding that led to the prediction that analogues of paclitaxel lacking any D ring could stabilize microtubules as well as paclitaxel if the substituent present at C4 did not have unfavorable steric interactions with the binding pocket. We report the synthesis of a 4-methyl paclitaxel analogue, compound 1, which bears this prediction out. Compound 1 is as potent as paclitaxel at microtubule stabilization in vitro; however, it has only about one-four-hundredth the cytotoxicity of paclitaxel.
Liver X receptors (LXRs) are nuclear receptors that participate in the regulation of cholesterol, bile acid, and glucose metabolism. Despite the identification of the natural oxysterol and nonsteroidal ligands for LXRalpha, little is known about the structure of the LXRalpha ligand-binding domain (LBD). We constructed a three-dimensional (3D) homology model of the LBD of LXRalpha based on the crystal structure of the retinoic acid receptor gamma (RARgamma) and all-trans retinoic acid complex. We combined molecular modeling and classical structure-function techniques to define the interactions between the LBD and three structurally diverse ligands, 22(R)-hydroxycholesterol (22RHC), N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-benzenesulfonamide (T0901317) and (3-[3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy]-phenyl)-acetic acid (GW3965). Sixteen individual amino acid point mutations were made in the predicted ligand-binding cavity of the LBD, and each of these mutant receptors was assessed for their ability to be activated by these three ligands. The majority of individual mutations resulted in lack of activation by all three ligands. Two residues were identified that resulted in a significant increase in basal activity while retaining responsiveness to the ligands. Interestingly, a number of residues were identified that appear to be selective in their response to a particular ligand, indicating that these three ligands recognize distinct structural components within the ligand-binding cavity. These data, together with our docking study, enable us to identify the amino acids that coordinate the interaction of both steroidal and non-steroidal ligands in the ligand-binding pocket of LXRalpha.
The aim of this study is to evaluate the effect of treatment with the Molecular Adsorbent Recirculating System (MARS) on liver failure based on HBV. In 25 patients (median age, 36.3 years, range, 22-67 years, bilirubin level > 255 micro mol/l) admitted with liver failure based on HBV, the 6-8h MARS intermittent treatments were performed without any adverse events, A significant decrease in bilirubin, ammonia and urea levels were observed (P < 0.05). All patients achieved a remarkable neurologic recovery, particularly 2 HE-III and 3 HE-IV patients regained normal consciousness, respectively. The survival rate for the patients whose treatments kept to the MARS art strategy was 76.9% (10/13), while the others only had the survival rate of 16.7% (2/12) due to their giving up sequential MARS treatments after the first time. The rebounding rate of the bilirubin level in the patients after a single MARS treatment was significantly lower than that of patients, who underwent a single plasma-exchange treatment (P < 0.01). It is concluded that MARS method can contribute to the optimistic treatment of liver failure patients based on HBV which being the major epidemic liver disease in China.
BACKGROUND: Poisoning by cytotoxic mushrooms (Amanita phalloides and related species) is associated with severe morbidity and a high mortality rate (lethality > 20% in adults and > 50% in children). The main causes of this intoxication are the amatoxines, which inhibit DNA-dependent RNA Polymerase II or B. This interaction leads to a tight complex, and the inhibition is of a non-competitive type (1); in addition to those tight binding inhibitors of adenosine kinase, papain, cathepsin L, cathepsin B, cysteine proteinase and bromelain (2), inhibit the synthesis of messenger RNA in the hepatocytes, decrease the formation of coagulation factors and of immunoglobulins and effect a vasoconstriction. They also have an influence on the transcription and lesions that are seen in cells with rapid protein synthesis, particularly in liver and renal cells, with the cellular changes causing the fragmentation and segregation of all nuclear components, even at low toxin concentrations (3). Phallotoxin, which is the other toxin isolated from death cap, binds with a high affinity to microfilamentous structures - in particular, to F-actin, which stimulates the polymerization of G-actin, stabilizes the F-actin filaments, irreversibly polymerizes actin filaments and causes cholestasis (4). Liver is recognized as the target organ for Amanita phalloides toxins; it is presented by fatty degeneration, acute toxic dystrophy and centrilobular necroses (5). Therapeutic options employed to treat mushroom intoxication, such as hemodiaperfusion on activated charcoal, high dosages of penicillin G, oral charcoal, etc., very often failed to act properly and liver transplantation (when a graft is available) appeared to be the only solution. The most polarized debate concerns the value of extracorporeal elimination. Plasmapheresis and peritoneal dialysis proved much less useful for this purpose; neither haemodialysis (HD) nor haemoperfusion (HP) contributed to the clearance of amatoxin (6, 7). Recently, Stange et al. (8). introduced a new detoxication method (referred to as MARS) for protein-bound substances in patients with liver failure and grade III and IV hepatic encephalopathy. MARS was performed with an albumin-containing dialysate, which is recycled in a closed loop that contains a charcoal cartridge, an anion exchanger resin adsorber and a conventional haemodialyser. With dialysis using an albumin-containing dialysate, protein-bound substances, which are usually not sufficiently dialysable, can be eliminated. The treatments increase the rate of toxin elimination to the extent that the toxic exposure of highly susceptible cells, such as hepatocytes, is minimized. This leads to the surprise recovery of the poisoning patient, despite her severe condition, even as late as up to a week after mushroom ingestion.
BACKGROUND: Molecular mechanics (MM) and quantum chemical (QM) calculations are widely applied and powerful tools for the stereochemical and conformational investigations of molecules. The same methods have been extensively used to probe the conformational profile of Taxol (Figure 1) both in solution and at the beta-tubulin protein binding site. RESULTS: In the present work, the relative energies of seven conformations of Taxol derived from NMR and X-ray analyses were compared with a set of widely used force fields and semiempirical MO methods coupled to a continuum solvent treatment. The procedures not only diverge significantly in their assessment of relative conformational energies, but none of them provide satisfactory agreement with experiment. CONCLUSIONS: For Taxol, molecular mechanics and semiempirical QM methods are unable to provide a consistent energetic ranking of side-chain conformations. For similar highly polar organic structures, "energy-free" conformational search methods are advised.
The human constitutive androstane receptor (hCAR; NR1I3) is a member of the nuclear receptor superfamily. The activity of hCAR is regulated by a variety of xenobiotics including clotrimazole and acetaminophen metabolites. hCAR, in turn, regulates a number of genes responsible for xenobiotic metabolism and transport including several cytochrome P450s (CYP 2B5, 2C9, and 3A4) and the multidrug resistance-associated protein 2 (MRP2, ABCC2). Thus, hCAR is believed to be a mediator of drug-drug interactions. We identified two novel hCAR splice variants: hCAR2 encodes a receptor in which alternative splice acceptor sites are utilized resulting in a 4 amino acid insert between exons 6 and 7, and a 5 amino acid insert between 7 and 8, and hCAR3 encodes a receptor with exon 7 completely deleted resulting in a 39 amino acid deletion. Both hCAR2 and hCAR3 mRNAs are expressed in a pattern similar to the initially described MB67 (hCAR1) with some key distinctions. Although the levels of expression vary depending on the tissue examined, hCAR2 and hCAR3 contribute 6-8% of total hCAR mRNA in liver. Analysis of the activity of these variants indicates that both hCAR2 and hCAR3 lose the ability to heterodimerize with RXR and lack transactivation activity in cotransfection experiments where either full-length receptor or GAL4 DNA-binding domain/CAR ligand binding domain chimeras were utilized. Although the role of hCAR2 and hCAR3 is currently unclear, these additional splice variants may provide for increased diversity in terms of responsiveness to xenobiotics.