Modular preparation of biphenyl triazoles via click chemistry as non-competitive hyaluronidase inhibitors.

Hyaluronidase is a promising target in drug discovery, given its overexpression in a range of physiological and pathological processes, including tumor migration, skin aging, sagging, and wrinkling, as well as inflammation and bacterial infections. In this study, to identify novel hyaluronidase inhibitors, we applied click chemistry for the modular synthesis of 370 triazoles in 96-well plates, starting with biphenyl azide. Utilizing an optimized turbidimetric screening assay in microplates, we identified Fmoc-containing triazoles 5 and 6, as well as quinoline-containing triazoles 15 and 16, as highly effective hyaluronidase inhibitors. Subsequent research indicated that these triazoles potentially interact with a novel binding site of hyaluronidase. Notably, these inhibitors displayed minimal cytotoxicity and showed promising anti-inflammatory effects in LPS-stimulated macrophages. Remarkably, compound 6 significantly reduced NO release by 74 % at a concentration of 20 µM.

Engineered assemblies from isomeric pentapeptides augment dry eye treatment.

Changing positions of amino acid residues in the peptide sequence alters the peptide' s assembly behaviors, affording various nanostructures. However, it remains elusive that how subtle changes in the peptide sequence influence the in vivo bioactivity of peptide-based nanocarriers, further impacting the efficacy of the encapsulated drugs. We report here a class of isomeric pentapeptide amphiphiles that associate into filaments with different dimensions, which were further used as carriers of Diquafosol tetrasodium (DQS), for the treatment of dry eye disease. Our results suggest that subtle changes in peptide sequences resulted in dramatically different molecular packings and distinct morphologies, which were verified by molecular dynamics simulations. In vivo results show that the drug retention time could be prolonged by the peptidic nanostructures on the ocular surface but were highly morphological-dependent. The longer retention time promised better therapeutic efficacy. In terms of facile synthesis and good biocompatibility, we believe that these peptides could be used for eye disease treatments or other related areas.

Molecular dynamics simulations reveal the inhibition mechanism of Cdc42 by RhoGDI1.

Cell division control protein 42 homolog (Cdc42), which controls a variety of cellular functions including rearrangements of the cell cytoskeleton, cell differentiation and proliferation, is a potential cancer therapeutic target. As an endogenous negative regulator of Cdc42, the Rho GDP dissociation inhibitor 1 (RhoGDI1) can prevent the GDP/GTP exchange of Cdc42 to maintain Cdc42 into an inactive state. To investigate the inhibition mechanism of Cdc42 through RhoGDI1 at the atomic level, we performed molecular dynamics (MD) simulations. Without RhoGDI1, Cdc42 has more flexible conformations, especially in switch regions which are vital for binding GDP/GTP and regulators. In the presence of RhoGDI1, it not only can change the intramolecular interactions of Cdc42 but also can maintain the switch regions into a closed conformation through extensive interactions with Cdc42. These results which are consistent with findings of biochemical and mutational studies provide deep structural insights into the inhibition mechanisms of Cdc42 by RhoGDI1. These findings are beneficial for the development of novel therapies targeting Cdc42-related cancers.

Advances in the development of Rho GTPase inhibitors.

Rho guanosine triphosphatases (Rho GTPases), as members of the Ras superfamily, are GDP/GTP binding proteins that behave as molecular switches for the transduction of signals from external stimuli. Rho GTPases play essential roles in a number of cellular processes including cell cycle, cell polarity as well as cell migration. The dysregulations of Rho GTPases are related with various diseases, especially with cancers. Accumulating evidence supports that Rho GTPases play important roles in cancer development and progression. Rho GTPases become potential therapeutic targets for cancer therapy. And a number of inhibitors targeting Rho GTPases have been developed. In this review, we discuss their structural features, summarize their roles in cancer, and focus on the recent progress of their inhibitors, which are beneficial for the drug discovery targeting Rho GTPases.

Validation of catalytic site residues of Ubiquitin Specific Protease 2 (USP2) by molecular dynamic simulation and novel kinetics assay for rational drug design.

Post-translational modifications of proteins such as protein ubiquitination are crucial for regulating conformation, stability and localization of the modified protein. Ubiquitin-specific protease 2 (USP2), a multifunctional cysteine protease is reported to be a key regulator of ubiquitylation events in numerous oncogenic proteins e.g., fatty acid synthetase, Mdm2, EGFR, cyclin A1, and cyclin-D1, etc. Thus targeting USP2 is a promising strategy for cancer therapy. USP2 is characterized by a catalytic triad comprising of cysteine, histidine and aspartic acid residues. Five residues including three from the catalytic triad and two from outside of the catalytic triad have been reported as a catalytic site of USP2 that catalyze hydrolysis and stabilizes the oxyanion formed in the intermediate step of catalysis. Here, we report two more novel residues (L269 and Y558) on USP2 involved in the catalysis of Ubiquitin using computational alanine scanning (CAS) followed by molecular dynamic simulation studies. The results obtained from CAS were further validated by a highly reliable, time- and cost-effective SDS-PAGE-based kinetics assay using UBA52 which is a natural substrate of USP2. Our results showed that mutating L269 and Y558 significantly compromised the catalytic efficiency of USP2 in hydrolyzing UBA52 which can further be extended to rational drug design of USP2 selective inhibitors and to explore the catalytic sites of other USPs. Two novel residues take part in catalytic activity of USP2 which were depicted by MD Simulations and were further validated by novel SDS-PAGE-based reliable time- and cost-effective kinetics assay.

Activation Mechanism of RhoA Caused by Constitutively Activating Mutations G14V and Q63L.

RhoA, a member of Rho GTPases, regulates myriad cellular processes. Abnormal expression of RhoA has been implicated in various diseases, including cancers, developmental disorders and bacterial infections. RhoA mutations G14V and Q63L have been reported to constitutively activate RhoA. To figure out the mechanisms, in total, 1.8 µs molecular dynamics (MD) simulations were performed here on RhoAWT and mutants G14V and Q63L in GTP-bound forms, followed by dynamic analysis. Both mutations were found to affect the conformational dynamics of RhoA switch regions, especially switch I, shifting the whole ensemble from the wild type's open inactive state to different active-like states, where T37 and Mg2+ played important roles. In RhoAG14V, both switches underwent thorough state transition, whereas in RhoAQ63L, only switch I was sustained in a much more closed conformation with additional hydrophobic interactions introduced by L63. Moreover, significantly decreased solvent exposure of the GTP-binding site was observed in both mutants with the surrounding hydrophobic regions expanded, which furnished access to water molecules required for hydrolysis more difficult and thereby impaired GTP hydrolysis. These structural and dynamic differences first suggested the potential activation mechanism of RhoAG14V and RhoAQ63L. Together, our findings complemented the understanding of RhoA activation at the atomic level and can be utilized in the development of novel therapies for RhoA-related diseases.

Discovery of oridonin as a novel agonist for BRS-3.

BACKGROUND: Bombesin Receptor Subtype-3 (BRS-3, Bombesin-like receptor, BB3) is an orphan G-protein coupled receptor (GPCR). Recent studies have shown that BRS-3 played a vital role in glucose regulation, insulin secretion, and energy homeostasis. Therefore, discovering more novel exogenous ligands with diverse structures for BRS-3 will be of great importance for target validation and drug development. PURPOSE: In this study, we aim to discover new agonists of BRS-3 from our natural compound libraries, providing a new probe to study the function of BRS-3. STUDY DESIGN: Multiple cell-based assays and in vivo experiments were performed to identify the new ligand. METHODS: BRS-3 overexpression cells were coupled with FLIPR assay, homogeneous time-resolved fluorescence (HTRF) IP-ONE assay, dynamic mass redistribution (DMR) assay, ß-arrestin2 recruitment assay, and western blot to determine receptor activation and downstream signaling events. To further validate the target of BRS-3, a series of in vitro and in vivo experiences were conducted, including glucose uptake, glucose transporter type 4 (GLUT4) transportation in C2C12, and oral glucose tolerance test (OGTT) in mice. RESULTS: We discovered and identified oridonin as a novel small molecule agonist of BRS-3, with a moderate affinity (EC50 of 2.236 × 10-7 M in calcium mobilization assay), specificity, and subtype selectivity. Further in vitro and in vivo tests demonstrated that oridonin exerted beneficial effects in glucose homeostasis through activating BRS-3. CONCLUSIONS: Oridonin, as the discovered new ligand of BRS-3, provides a valuable tool compound to investigate BRS-3's function, especially for target validation in type 2 diabetes and obesity. Oridonin is promising as a lead compound in the treatment of metabolic disorders. Compared to the known agonists of BRS-3, we can take advantage of the multiple reported pharmacological activities of ODN as a natural product and assess whether these pharmacological activities are regulated by BRS-3. This may facilitate the discovery of novel functions of BRS-3.

Molecular dynamics simulations reveal the activation mechanism of mutations G12V and Q61L of Cdc42.

Cell division control protein 42 homolog (Cdc42), which contributes to multiple cellular processes including cell proliferation and migration, is a potential target for cancer therapy, especially in the intervention of tumor migration. Cdc42's mutants G12V and Q61L are discovered constitutively active, and the overexpression of them exhibits oncogenic activities. Here, using molecular dynamics (MD) simulations and dynamic analysis, we illustrated the activation mechanism of Cdc42G12V and Cdc42Q61L . Without GAP, the two mutations differently elicited state transition from the wild-type's open "inactive" state 1 to the closed "active" state 2, induced by the introduction of a newly formed water-mediated T35-γ-phosphate hydrogen bond in G12V system and the additional hydrophobic interactions between L61 and T35 together with the direct T35-γ-phosphate hydrogen bond in Q61L system. When binding with GAP, both mutations weakened the hydrogen bond interactions between Cdc42-GTP and GAP's finger loop, and disturbed the catalytically competent organizations of GAP's catalytic R305/R306 and Cdc42's Q61, thereby impairing the GAP-mediated GTP hydrolysis. Our findings first reveal the activation mechanism of Cdc42's G12V and Q61L mutants on a molecular basis, which provide new insights into the structural and dynamical characteristics of Cdc42 and its mutants and can be exploited in the further development of novel therapies targeting Cdc42-related cancers.

Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening.

Anterior Gradient 2 (AGR2) has recently been reported as a tumor biomarker in various cancers, i.e., breast, prostate and lung cancer. Predominantly, AGR2 exists as a homodimer via a dimerization domain (E60-K64); after it is self-dimerized, it helps FGF2 and VEGF to homo-dimerize and promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts. Up till now, no small molecule has been discovered to inhibit the AGR2-AGR2 homodimer. Therefore, the present study was performed to prepare a validated 3D structure of AGR2 by homology modeling and discover a small molecule by screening the FDA-approved drugs library on AGR2 homodimer as a target protein. Thirteen different homology models of AGR2 were generated based on different templates which were narrowed down to 5 quality models sorted by their overall Z-scores. The top homology model based on PDB ID = 3PH9 was selected having the best Z-score and was further assessed by Verify-3D, ERRAT and RAMPAGE analysis. Structure-based virtual screening narrowed down the large library of FDA-approved drugs to ten potential AGR2-AGR2 homodimer inhibitors having FRED score lower than - 7.8 kcal/mol in which the top 5 drugs' binding stability was counter-validated by molecular dynamic simulation. To sum up, the present study prepared a validated 3D structure of AGR2 and, for the first time reported the discovery of 5 FDA-approved drugs to inhibit AGR2-AGR2 homodimer by using structure-based virtual screening. Moreover, the binding of the top 5 hits with AGR2 was also validated by molecular dynamic simulation. A validated 3D structure of Anterior Gradient 2 (AGR2) was prepared by homology modeling, which was used in virtual screening of FDA-approved drugs library for the discovery of prospective inhibitors of AGR2-AGR2 homodimer.

Tetraethylthiuram disulphide alleviates pulmonary fibrosis through modulating transforming growth factor-ß signalling.

Idiopathic pulmonary fibrosis (IPF) induces significant morbidity and mortality, for which there are limited therapeutic options available. Here, we found that tetraethylthiuram disulphide (disulfiram, DSF), a derivative of thiuram, used in the treatment of alcohol abuse, has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis via the attenuation of the fibroblast-to-myofibroblast transition, migration, and proliferation of fibroblasts. Furthermore, DSF inhibited the activation of primary pulmonary fibroblasts and fibroblast cell line under transforming growth factor-ß 1 (TGF-ß1) challenge. Mechanistically, the anti-fibrotic effect of DSF on fibroblasts depends on the inhibition of TGF-ß signalling. We further determined that DSF interrupts the interaction between SMAD3 and TGF-ß receptor Ι (TBR Ι), and identified that DSF directly binds with SMAD3, in which Trp326, Thr330, and Cys332 of SMAD3 are critical binding sites for DSF. Collectively, our results reveal a powerful anti-fibrotic function of DSF in pulmonary fibrosis through the inhibition of TGF-ß/SMAD signalling in pulmonary fibroblasts, indicating that DSF is a promising therapeutic candidate for IPF.

Benzothiophene-2-carboxamide derivatives as SENPs inhibitors with selectivity within SENPs family.

The SUMO (small ubiquitin-related modifier)-specific proteases (SENPs) are responsible for the cleavage of SUMO from its target proteins, thus play important roles in the dynamic SUMOylation and deSUMOylation processes. SENPs are related to a variety of human diseases including cancer and represent a new class of potential therapeutic targets with mechanism of action that is likely to be different from that of current clinically used drugs. However, potent inhibitors that are selective within the SENPs family members still remain a challenge due to their high homology. In order to demonstrate the feasibility of developing selective inhibitors within the SENPs family, we chose SENP1/2/5 as representatives, aiming to identify inhibitors with selectivity among the members. Starting from a hit compound ZCL951 from virtual screening, a series of benzothiophene-2-carboxamide inhibitors were designed based on the protein structures of SENP1, 2, and 5. First, an unoccupied hydrophobic pocket was first identified which led to IC50 as low as 0.56 µM. Furthermore, the ethylacetate 77 gave both submicromolar inhibitory activity and 33-fold selectivity for SENP2 versus SENP5. They are the most potent and selective nonpeptidic inhibitor reported so far for the SENPs family, as far as we are aware. Their structure-activity relationship was also discussed.

Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease with limited therapeutic strategies. Lycorine (LYC), an alkaloid isolated from Amaryllidaceae family plants, exhibits effective anti-inflammatory, antiviral, and anti-tumor activities. In this study, we attempted to determine the effect of LYC on bleomycin (BLM)-induced IPF and NLRP3 inflammasome activation. Our results demonstrated that the LYC treatment ameliorated BLM-induced pulmonary fibrosis and inflammation in mice. LYC inhibited active Caspase-1 expression and lactate dehydrogenase (LDH) release during BLM-induced acute lung injury (ALI) in mice. Furthermore, our in vitro assay showed that LYC inhibited LPS/Nigericin- or LPS/ATP-induced NACHT, LRP and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pyroptosis in bone marrow-derived macrophages (BMDMs). Mechanically, LYC could disturb the interaction of NLRP3 with apoptosis-associated speck-like protein containing a CARD (ASC) by targeting the pyrin domain (PYD) on Leu9, Leu50, and Thr53. Our findings indicate that LYC ameliorated BLM-induced pulmonary fibrosis by inhibiting NLRP3 inflammasome activation and pyroptosis through targeting the PYD domain of ASC. Thus, LYC might be a potential therapeutic agent for pulmonary inflammation and fibrosis.

Mechanisms of transformation of nicotinamide mononucleotides to cerebral infarction hemorrhage based on MCAO model.

OBJECTIVE: The study aims at discussing the effect of nicotinamide mononucleotides on protecting hemorrhagic transformation of cerebral infarction in the middle cerebral artery occlusion (MCAO) model. METHOD: Male mice aged 4-5 weeks and weighing about 22-35 g in Shanghai Ninth People's Hospital are divided into three groups: sham group, collagenase intracerebral hemorrhage model (cICH + Vehicle) group and collagenase nicotinamide mononucleotide (cICH + NMN) group. Then, the intervention therapy research is carried out. After 24 h, the neurological function, brain edema, hematoma volume, body weight, hemorrhage volume, RNA expression level, apoptosis, inflammatory factors and reactive oxygen species (ROS) content in surrounding tissues of mice are analyzed comprehensively. RESULTS: Compared with the other two groups, nicotinamide mononucleotides in MCAO model have significant effects on improving neurological function, brain edema, inflammatory factors, body weight and cell apoptosis in mice, but have no significant effect on hemorrhage volume and hematoma volume in mice. CONCLUSION: Nicotinamide mononucleotides can significantly improve the collagenase-induced intracerebral hemorrhage (ICH) model in mice under MCAO model, and they can protect the brain tissue of mice from RNA level to tissue cell level or mouse body weight and volume level.

Polydopamine Nanoparticles for Deep Brain Ablation via Near-Infrared Irradiation.

Local resection or ablation remains an important approach to treat drug-resistant central neurological disease. Conventional surgical approaches are designed to resect the diseased tissues. The emergence of photothermal therapy (PTT) offers a minimally invasive alternative. However, their poor penetration and potential off-target effect limit their clinical application. Here, polydopamine nanoparticles (PDA-NPs) were prepared and characterized. Studies were performed to evaluate whether PDA-NPs combined with near-infrared (NIR) light can be used to ablate deep brain structures in vitro and in vivo. PDA-NPs were prepared with a mean diameter of ∼150 nm. The particles show excellent photothermal conversion efficiency. PDA-NPs did not show remarkable cytotoxicity against neuronal-like SH-SY5Y cell lines. However, it can cause significant cell death when combined with NIR irradiation. Transcranial NIR irradiation after PDA-NPs administration induced enhanced local hyperthermia as compared with NIR alone. Local temperature exceeded 60 °C after 6 min of irradiation plus PDA while it can only reach 48 °C with NIR alone. PTT with PDA (10 mg/mL, 3 µL) and NIR (1.5 W/cm2) can ablate deep brain structures precisely with an ablation volume of ∼6.5 mm3. Histological analysis confirmed necrosis and apoptosis in the targeted area. These results demonstrate the potential of NP-assisted PTT for the treatment against nontumorous central neurological diseases.

Discovery of small molecule agonists targeting neuropeptide Y4 receptor using homology modeling and virtual screening.

Neuropeptide Y4 receptor has the most significant effect on body weight and fat mass in its physiological functions, and the activation of Y4 receptor has explicit role on losing weight. The Y4 receptor has been successfully applied in the development of anti-obesity agent, thus representing a potential therapeutic target for obesity treatment. Here, we reported the first discovery of small molecule agonists targeting Y4 receptor: three Y4 receptor models with active and inactive conformations were built, each model was submitted following structure-based virtual screening, and finally six hits were identified as Y4 receptor agonists. These results confirm the reliability of the constructed Y4 receptor models and the proposed computational strategy for investigating novel Y4 receptor agonists. These new small molecule Y4 receptor agonists will contribute to the further development of Y4 agonists as potential therapeutics and functional probes.

Inhibition of Cdc42-intersectin interaction by small molecule ZCL367 impedes cancer cell cycle progression, proliferation, migration, and tumor growth.

Cdc42 is a member of the Rho family of small GTPases that are at the crossroads of major oncogenic signaling pathways involved in both lung and prostate cancers. However, the therapeutic potential of Cdc42 regulation is still unclear due to the lack of pharmacological tools. Herein, we report that ZCL367 is a bona fide Cdc42 inhibitor that suppressed cancer development and ZCL278 can act as a partial Cdc42 agonist. In lung cancer cell lines with varying EGFR and Ras mutations as well as both androgen-independent and androgen-dependent prostate cancer cell lines, ZCL367 impeded cell cycle progression, reduced proliferation, and suppressed migration. ZCL367 decreased Cdc42-intersectin interactions and reduced Cdc42-mediated filopodia formation. ZCL367 showed increased potency and selectivity for Cdc42 when compared to Rac1 and RhoA. ZCL367 reduced A549 tumorigenesis in a xenograft mouse model. Altogether, ZCL367 is a selective Cdc42 inhibitor and an excellent candidate for lead compound optimization for further anticancer studies.

Dissociation mechanism of GDP from Cdc42 via DOCK9 revealed by molecular dynamics simulations.

Cell division control protein 42 homolog (Cdc42) influences a variety of cellular responses such as cell migration and polarity. Deregulation of Cdc42 has been associated with several human diseases and developmental disorders. Over-activation of Cdc42 through guanine nucleotide exchange factor (GEF) is a critical event for Cdc42 involved cancer metastasis. Members of DOCK family of GEF are important activators of Cdc42. However, this activation mechanism is still unknown. Molecular dynamics (MD) simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) calculations were employed to investigate the central step of the activation of Cdc42: the dissociation mechanism of GDP from Cdc42 via DOCK9. Simulation results show that Mg2+ ion has a remarkable influence on the conformational change of switch I of Cdc42 through residue Pro34 which functions as a "clasp" to control the flexibility of switch I. In the GDP dissociation process, the Mg2+ ion leave first to result in a suitable conformation of Cdc42 for following DOCK9 binding to. When DOCK9 binds to Cdc42, it changes the orientations of residues Lys16, Thr17, Cys18 and Phe28 of Cdc42 to weaken the interactions between Cdc42 and GDP to release GDP. This study first elucidates the dissociation mechanism of GDP from Cdc42 via DOCK9 and identifies the essential residues of Cdc42 in this process. These simulation results are consistent with the recent findings of biochemical and amino acid mutational studies, and the observations are beneficial to understand the activation mechanism of Cdc42 and to provide insights for designing compounds targeting on Cdc42 related cancer metastasis.

Effectiveness of Screening Modalities in Colorectal Cancer: A Network Meta-Analysis.

The aim of the study was to evaluate on the effectiveness of screening modalities in the prevention of colorectal cancer (CRC) occurrence and deaths. General meta-analysis was performed to produce pooled estimates of the effect of CRC incidence and mortality using a search of PubMed, Web of Science, and the Cochrane Library for eligible studies from January 1992 to March 2016. A network meta-analysis was performed to synthetically compare the effectiveness of 5 frequently used screening modalities. A total of 44 studies with a focus on mortality from CRC using different screening methods were included. General meta-analysis showed that fecal immunohistochemical testing (FIT), flexible sigmoidoscopy (FS), colonoscopy, combination of fecal occult blood testing and FS screening respectively reduced CRC mortality by 59% (relative risk [RR], 0.41; 95% confidence interval [CI], 0.29-0.59), 33% (RR, 0.67; 95% CI, 0.58-0.78), 61% (RR, 0.39; 95% CI, 0.31-0.50), 38% (RR, 0.62; 95% CI, 0.42-0.91) compared with no screening, whereas guaiac fecal occult blood testing (gFOBT) reduced CRC-related mortality by 14% (RR, 0.86; 95% CI, 0.82-0.90). Subgroup analysis showed that summary estimates of reduction in distal CRC mortality and proximal CRC mortality were 26% (95% CI, 62%-89%) and 10% (95% CI, 83%-98%). A network meta-analysis revealed rank probability analysis in which the colonoscopy had a 94.6% probability of being the most effective examination to reduce CRC mortality. In addition, the network meta-analysis estimated odds ratio, which was a 79% reduction (95% CI, 0.09-0.60) in CRC mortality when screening with FIT was compared with annual or biennial gFOBT and colonoscopy was approximately 80% more effective than gFOBT for reducing CRC mortality (RR, 0.25; 95% CI, 0.13-0.54). Analysis of the effects of different screening methods showed that there was a significant reduction in the incidence of colon cancer, excluding gFOBT. This meta-analysis confirmed that gFOBT, FIT, FS, and colonoscopy were all effective in preventing CRC deaths and a major reduction in distal but not proximal CRC mortality was found. In addition, they were more effective in preventing CRC incidence in addition to gFOBT. The network meta-analysis suggests that colonoscopy is the most effective screening for preventing CRC deaths.

Efficacy and safety of long-term treatment with statins for coronary heart disease: A Bayesian network meta-analysis.

BACKGROUND AND AIMS: Our study aims to evaluate the efficacy and safety of long-term treatment of statins for coronary heart disease (CHD). METHODS: Efficacy outcomes included changes in blood lipids, risk of CHD mortality and all-cause mortality. Safety outcomes were evaluated by the risk of adverse events (AE). Bayesian network meta-analysis was used to compare the direct and indirect effects between different statins. RESULTS: The systematic review showed that levels of blood lipids decreased during statin treatment. High dose of atorvastatin was the most obvious treatment for the reduction of blood lipids. Network meta-analysis showed that statins were significantly more effective than the control in reducing the risk of CHD mortality (Odds Ratio (OR) 0.69, 95% CI 0.61-0.77) and all-cause mortality (OR 0.84, 95% CI 0.80-0.87). In terms of reducing the risk of CHD morality, fluvastatin (77.3%), atorvastatin (72.3%) and lovastatin (68.4%) had higher cumulative probability than other statins, which were more effective treatments for the reduction of CHD morality. In terms of reducing all-cause mortality, atorvastatin (78.6%), fluvastatin (77.1%) and pitavastatin (74.1%) had higher cumulative probability than other statins, which were more effective treatment for reducing the all-cause mortality. Compared with placebo, statins increased the incidence risk of muscle disease (OR 1.05, 95% CI 1.00-1.10) and kidney disease (OR 1.11, 95% CI 1.05-1.72). CONCLUSIONS: Statins significantly reduced levels of blood lipids, with a high dose of atorvastatin being the most effective in blood-lipid level modification. Statins reduced the risk of CHD mortality and all-cause mortality, with atorvastatin and fluvastatin being the most effective in reducing the risk of CHD mortality and all-cause mortality. Statins increased the risk of muscle disease and kidney damage.

Identification of SENP1 inhibitors through in silico screening and rational drug design.

The small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) catalyze the deconjugation of SUMO from their substrate proteins. SENP1 which is the most studied isoform is closely related to many cancers such as prostate cancer and colon cancer, thus representing a potential therapeutic target for cancer treatment. In the present study, we identified eleven SENP1 inhibitors representing a variety of scaffolds through in silico screening. Based on these scaffolds, a series of new compounds were designed and synthesized in order to improve their SENP1 inhibitory potency. As a result, compounds with IC50 as low as 3.5 µM (compound 13m) were obtained and a preliminary structure-activity relationship was discussed.