294 research outputs found

    Accurate prediction of ligand binding for a flexible protein using P-score ranking.

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    Protein ligand binding prediction typically relies on docking methodologies and associated scoring functions to propose the binding mode of a ligand in a biological target. Significant challenges are associated with this approach, including the flexibility of the protein-ligand system, solvent-mediated interactions and associated entropy changes. In addition, scoring functions are only weakly accurate due to the short time required for calculating enthalpic and entropic binding interactions. The workflow described here attempts to address these limitations by combining Supervised Molecular Dynamics (SuMD) with Dynamical Averaging Quantum Mechanics Fragment Molecular Orbital (DA-QM-FMO). This is illustrated using a set of five ligands targeting the SARS-CoV-2 Papain-like protease protein. This combination significantly increased the ability to predict the experimental binding structure of protein-ligand complexes independent from the starting position of the ligands or the binding site conformation. We found that the predictive power could be enhanced by combining the residence time (SuMD) and interaction energies (DA-QM-FMO) as descriptors in a novel scoring function named the P-score

    The prescriber's guide to classic MAO-inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression

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    This article is a clinical guide which discusses the state-of-The-Art usage of the classic MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI-prescribers. It discusses indications, drug drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (over 70 international expert129 endorsers), based on six decades of experience, for the recommendations herein exposited. They are based on empirical evidence and on expert opinion this guide is presented as a new specialist131 consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to ECT whilst taking account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some TCAs. It also illustrates the straightforward bridging methods that may be used to transition simply and safely from other antidepressants to MAOIs

    The prescriber's guide to classic MAO-inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression

    No full text
    This article is a clinical guide which discusses the state-of-The-Art usage of the classic MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI-prescribers. It discusses indications, drug drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (over 70 international expert129 endorsers), based on six decades of experience, for the recommendations herein exposited. They are based on empirical evidence and on expert opinion this guide is presented as a new specialist131 consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to ECT whilst taking account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some TCAs. It also illustrates the straightforward bridging methods that may be used to transition simply and safely from other antidepressants to MAOIs

    Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial

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    Background: Pompe disease is a rare disorder characterised by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. We aimed to assess the safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabiliser) for late-onset Pompe disease. Methods: We did a randomised, double-blind, parallel-group, phase 3 trial at 62 neuromuscular and metabolic medical centres in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease, and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov, NCT03729362. Findings: Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI −2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths. Interpretation: Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses. Funding: Amicus Therapeutics

    Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab: subgroup analysis of REGAIN and its extension study

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    Introduction/Aims: Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti-acetylcholine receptor antibody-positive (AChR+) gMG previously treated with rituximab. Methods: This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open-label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. Results: Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous-rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no-previous-rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous-rituximab and no-previous-rituximab groups (least-squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least-squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post-intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. Discussion: Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously

    Natural products in drug discovery: advances and opportunities

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    none73siNatural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities.noneAtanasov A.G.; Zotchev S.B.; Dirsch V.M.; Orhan I.E.; Banach M.; Rollinger J.M.; Barreca D.; Weckwerth W.; Bauer R.; Bayer E.A.; Majeed M.; Bishayee A.; Bochkov V.; Bonn G.K.; Braidy N.; Bucar F.; Cifuentes A.; D'Onofrio G.; Bodkin M.; Diederich M.; Dinkova-Kostova A.T.; Efferth T.; El Bairi K.; Arkells N.; Fan T.-P.; Fiebich B.L.; Freissmuth M.; Georgiev M.I.; Gibbons S.; Godfrey K.M.; Gruber C.W.; Heer J.; Huber L.A.; Ibanez E.; Kijjoa A.; Kiss A.K.; Lu A.; Macias F.A.; Miller M.J.S.; Mocan A.; Muller R.; Nicoletti F.; Perry G.; Pittala V.; Rastrelli L.; Ristow M.; Russo G.L.; Silva A.S.; Schuster D.; Sheridan H.; Skalicka-Wozniak K.; Skaltsounis L.; Sobarzo-Sanchez E.; Bredt D.S.; Stuppner H.; Sureda A.; Tzvetkov N.T.; Vacca R.A.; Aggarwal B.B.; Battino M.; Giampieri F.; Wink M.; Wolfender J.-L.; Xiao J.; Yeung A.W.K.; Lizard G.; Popp M.A.; Heinrich M.; Berindan-Neagoe I.; Stadler M.; Daglia M.; Verpoorte R.; Supuran C.T.Atanasov, A. G.; Zotchev, S. B.; Dirsch, V. M.; Orhan, I. E.; Banach, M.; Rollinger, J. M.; Barreca, D.; Weckwerth, W.; Bauer, R.; Bayer, E. A.; Majeed, M.; Bishayee, A.; Bochkov, V.; Bonn, G. K.; Braidy, N.; Bucar, F.; Cifuentes, A.; D'Onofrio, G.; Bodkin, M.; Diederich, M.; Dinkova-Kostova, A. T.; Efferth, T.; El Bairi, K.; Arkells, N.; Fan, T. -P.; Fiebich, B. L.; Freissmuth, M.; Georgiev, M. I.; Gibbons, S.; Godfrey, K. M.; Gruber, C. W.; Heer, J.; Huber, L. A.; Ibanez, E.; Kijjoa, A.; Kiss, A. K.; Lu, A.; Macias, F. A.; Miller, M. J. S.; Mocan, A.; Muller, R.; Nicoletti, F.; Perry, G.; Pittala, V.; Rastrelli, L.; Ristow, M.; Russo, G. L.; Silva, A. S.; Schuster, D.; Sheridan, H.; Skalicka-Wozniak, K.; Skaltsounis, L.; Sobarzo-Sanchez, E.; Bredt, D. S.; Stuppner, H.; Sureda, A.; Tzvetkov, N. T.; Vacca, R. A.; Aggarwal, B. B.; Battino, M.; Giampieri, F.; Wink, M.; Wolfender, J. -L.; Xiao, J.; Yeung, A. W. K.; Lizard, G.; Popp, M. A.; Heinrich, M.; Berindan-Neagoe, I.; Stadler, M.; Daglia, M.; Verpoorte, R.; Supuran, C. T

    Natural products in drug discovery: advances and opportunities

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    Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities

    Natural products in drug discovery: advances and opportunities

    No full text
    Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities. © 2021, Springer Nature Limited

    Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

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    OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo
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