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As drug‐binding kinetics has become an important factor to be considered in modern drug discovery, this work evaluated the ability of the Milestoning method in computing the absolute dissociation rate of a ligand from the serine–threonine kinase, glycogen synthase kinase 3β, which is a target for designing drugs to treat diseases such as neurodegenerative disorders and diabetes. We found that the Milestoning method gave good agreement with experiment with modest computational costs. Although the time scale for dissociation lasted tens of seconds, the collective molecular dynamics simulations total less than 1μs. Computing the committor function helped to identify the transition states (TSs), in which the ligand moved substantially away from the binding pocket. The glycine‐rich loop with a serine residue attaching to its tips was found to undergo large movement from the bound to the TSs and might play a role in controlling drug‐dissociation kinetics. [ABSTRACT FROM AUTHOR]

Early‐stage drug discovery projects often focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. The kinetics of drug binding are ignored but can have significant influence on drug efficacy. Therefore, increasing attention has been paid on evaluating drug‐binding kinetics early in a drug discovery process. Simulating drug‐binding kinetics at the atomic level is challenging for the long time scale involved. Here, we used the transition‐based reweighting analysis method (TRAM) with the Markov state model to study the dissociation of a ligand from the protein kinase PYK2. TRAM combines biased and unbiased simulations to reduce computational costs. This work used the umbrella sampling technique for the biased simulations. Although using the potential of mean force from umbrella sampling simulations with the transition‐state theory over‐estimated the dissociation rate by three orders of magnitude, TRAM gave a dissociation rate within an order of magnitude of the experimental value. [ABSTRACT FROM AUTHOR]

Summary: Identifying surgical patients with obstructive sleep apnoea may assist with anaesthetic management to minimise postoperative complications. Using trial sequential analysis, we evaluated the impact of obstructive sleep apnoea diagnosed by polysomnography or home sleep apnoea testing on postoperative outcomes in surgical patients. Multiple databases were systematically searched. Outcomes included: total postoperative complications, systemic complications (cardiovascular, respiratory, neurological, renal, infectious) and specific complications (atrial fibrillation, myocardial infarction, combined hospital and intensive care unit re‐admission, mortality). The pooled odds ratios of postoperative complications were evaluated by the Mantel–Haenszel method random‐effects model. Meta‐analysis and meta‐regression were conducted, and the GRADE approach was used to evaluate the certainty of evidence. Twenty prospective cohort studies with 3756 patients (2127 obstructive sleep apnoea and 1629 non‐obstructive sleep apnoea) were included (9 in non‐cardiac surgery and 11 in cardiac surgery). Postoperative complications were almost two‐fold higher with obstructive sleep apnoea, OR (95%CI) 1.92 (1.52–2.42), p < 0.001; certainty of evidence, moderate. Obstructive sleep apnoea was associated with a 1.5 times increased risk of postoperative cardiovascular complications, OR (95%CI) 1.56 (1.20–2.02), p = 0.001; certainty of evidence, moderate; an almost two‐fold increase in respiratory complications, OR (95%CI) 1.91 (1.39–2.62), p < 0.001; certainty of evidence, moderate; and hospital and ICU re‐admission, OR (95%CI) 2.25 (1.21–4.19), p = 0.01; certainty of evidence, low. Trial sequential analysis showed adequate information size for postoperative complications. Baseline confounding factors were adjusted by meta‐regression, and the sub‐group analysis did not materially change our results. This increased risk occurred especially in patients in whom obstructive sleep apnoea had been newly diagnosed, emphasising the importance of pre‐operative screening. [ABSTRACT FROM AUTHOR]

EDock‐ML is a web server that facilitates the use of ensemble docking with machine learning to help decide whether a compound is worthwhile to be considered further in a drug discovery process. Ensemble docking provides an economical way to account for receptor flexibility in molecular docking. Machine learning improves the use of the resulting docking scores to evaluate whether a compound is likely to be useful. EDock‐ML takes a bottom‐up approach in which machine‐learning models are developed one protein at a time to improve predictions for the proteins included in its database. Because the machine‐learning models are intended to be used without changing the docking and model parameters with which the models were trained, novice users can use it directly without worrying about what parameters to choose. A user simply submits a compound specified by an ID from the ZINC database (Sterling, T.; Irwin, J. J., J Chem Inf Model 2015, 55[11], 2,324–2,337.) or upload a file prepared by a chemical drawing program and receives an output helping the user decide the likelihood of the compound to be active or inactive for a drug target. EDock‐ML can be accessed freely at edock‐ml.umsl.edu [ABSTRACT FROM AUTHOR]

Ensemble docking has provided an inexpensive method to account for receptor flexibility in molecular docking for virtual screening. Unfortunately, as there is no rigorous theory to connect the docking scores from multiple structures to measured activity, researchers have not yet come up with effective ways to use these scores to classify compounds into actives and inactives. This shortcoming has led to the decrease, rather than an increase in the performance of classifying compounds when more structures are added to the ensemble. Previously, we suggested machine learning, implemented in the form of a naïve Bayesian model could alleviate this problem. However, the naïve Bayesian model assumed that the probabilities of observing the docking scores to different structures to be independent. This approximation might prevent it from achieving even higher performance. In the work presented in this paper, we have relaxed this approximation when using several other machine learning methods—k nearest neighbor, logistic regression, support vector machine, and random forest—to improve ensemble docking. We found significant improvement. [ABSTRACT FROM AUTHOR]

Drug‐binding kinetics could play important roles in determining the efficacy of drugs and has caught the attention of more drug designers. Using the dissociation of 1H‐pyrrolo[2,3‐b]‐pyridines from the focal adhesion kinase as an example, this work finds that steered molecular dynamics simulations could help screen compounds with long‐residence times. It also reveals a two‐step mechanism of ligand dissociation resembling the release of ADP from protein kinase A reported earlier. A phenyl group attaching to the pyrrole prolongs residence time by creating a large activation barrier for transition from the bound to the intermediate state when it becomes exposed to the solvent. Principal component analysis shows that ligand dissociation does not couple with large‐scale collective motions of the protein involving many of its amino acids. Rather, a small subset of amino acids dominates. Some of these amino acids do not contact the ligands directly along the dissociation pathways and could exert long‐range allosteric effects. © 2018 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

☛ CPD available at http://www.learnataagbi.org [ABSTRACT FROM AUTHOR]

This short article examines the usefulness of fast simulations of conformational transition paths in elucidating enzymatic mechanisms and guiding drug discovery for protein kinases. It applies the transition path method in the MOIL software package to simulate the paths of conformational transitions between six pairs of structures from the Protein Data Bank. The structures along the transition paths were found to resemble experimental structures that mimic transient structures believed to form during enzymatic catalysis or conformational transitions, or structures that have drug candidates bound. These findings suggest that such simulations could provide quick initial insights into the enzymatic mechanisms or pathways of conformational transitions of proteins kinases, or could provide structures useful for aiding structure-based drug design. [ABSTRACT FROM AUTHOR]

The authors assert the need to incorporate smoking cessation interventions into the routine pre-operative and post-operative care of surgical patients at all hospitals. They said greater support is necessary for the implementation of peri-operative smoking cessation interventions in a systemic fashion. The authors add that a major change in the culture of anaesthetists is necessary.

Extending a previous mining-minima approach to identifying the docking pathways between the hexapeptide GDYMNM and the catalytic domain of the insulin receptor tyrosine kinase (IRK), we found two major docking pathways connecting the binding pocket and the surface of the protein. One pathway was more likely to lead to phosphate transfer from ATP to the peptide as the distance between the γ-phosphate of ATP and the hydroxyl oxygen of the target tyrosine approached one that could facilitate reaction. The movement of the peptide along the pathways was found to couple with residues in the activation loop of the protein. Although these residues might not affect binding affinity, they might influence the kinetics of peptide entrance and release. Proteins 2012; © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Yersinia pestis causes diseases ranging from gastrointestinal syndromes to bubonic plague and could be misused as a biological weapon. As its protein tyrosine phosphatase YopH has already been demonstrated as a potential drug target, we have developed two series of forty salicylic acid derivatives and found sixteen to have micromolar inhibitory activity. We designed these ligands to have two chemical moieties connected by a flexible hydrocarbon linker to target two pockets in the active site of the protein to achieve binding affinity and selectivity. One moiety possessed the salicylic acid core intending to target the phosphotyrosine-binding pocket. The other moiety contained different chemical fragments meant to target a nearby secondary pocket. The two series of compounds differed by having hydrocarbon linkers with different lengths. Before experimental co-crystal structures are available, we have performed molecular docking to predict how these compounds might bind to the protein and to generate structural models for performing binding affinity calculation to aid future optimization of these series of compounds. [ABSTRACT FROM AUTHOR]

Background and Purpose: Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina.Experimental Approach: Mid-gestational (day 75 +/- 13, n= 7) and late-gestational (day 150 +/- 10, n= 5) age macaques were imaged after administration of a prototypic P-gp substrate, (11)C-verapamil (13.7-75.4 MBq.kg(-1)), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg.kg(-1).h(-1)). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0-9 min) under the (11)C-radioactivity concentration-time curve in the tissue (AUC(tissue)) to that in the maternal plasma (AUC(plasma)).Key Results: The CsA-induced change in AUC(fetal liver)/AUC(maternal)(plasma) of (11)C-radioactivity significantly increased from mid- (35 +/- 25%) to late gestation (125 +/- 66%). Likewise, the CsA-induced change in AUC(maternal brain)/AUC(plasma) increased from mid- (172 +/- 80%) to late gestation (337 +/- 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating (11)C-verapamil metabolites were significantly affected by gestational age.Conclusions and Implications: P-gp activity at the blood-brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy. [ABSTRACT FROM AUTHOR]

Protein kinases have high structural plasticity: their structure can change significantly, depending on what ligands are bound to them. Rigid-protein docking methods are not capable of describing such effects. Here, we present a new flexible-ligand flexible-protein docking model in which the protein can adopt conformations between two extremes observed experimentally. The model utilized a molecular dynamics-based simulated annealing cycling protocol and a distance-dependent dielectric model to perform docking. By testing this model on docking four diverse ligands to protein kinase A, we found that the ligands were able to dock successfully to the protein with the proper conformations of the protein induced. By imposing relatively soft conformational restraints to the protein during docking, this model reduced computational costs yet permitted essential conformational changes that were essential for these inhibitors to dock properly to the protein. For example, without adequate movement of the glycine-rich loop, it was difficult for the ligands to move from the surface of the protein to the binding site. In addition, these simulations called for better ways to compare simulation results with experiment other than using the popular root-mean-square deviation between the structure of a ligand in a docking pose and that in experiment because the structure of the protein also changed. In this work, we also calculated the correlation coefficient between protein–ligand/protein–protein distances in the docking structure and those in the crystal structure to check how well a ligand docked into the binding site of the protein and whether the proper conformation of the protein was induced. © 2008 Wiley Periodicals, Inc. J Comput Chem 2009 [ABSTRACT FROM AUTHOR]

By docking flexible balanol to a rigid model of protein kinase A (PKA), we found that a new simulated annealing protocol termed disrupted velocity simulated annealing (DIVE-SA) outperformed the replica-exchange method and the traditional simulated annealing method in identifying the correct docking pose. In this protocol, the atomic velocities were reassigned periodically to encourage the system to sample a large conformational space. We also found that scaling potential energy surface to reduce structural transition barriers could further facilitate docking. The DIVE-SA method was then evaluated on its ability to perform flexible ligand-flexible protein docking of three ligands (balanol, a balanol analog, and ATP) to PKA. To reduce computational time and to avoid possible unphysical structural changes resulting from the use of nonoptimal force fields, a soft restrain was applied to keep the root-mean-square-deviation (RMSD) between instantaneous protein structures and a chosen reference structure small. Because the restrain was applied to the overall RMSD rather than to individual atoms, a protein could still experience relatively large conformational changes during docking. To examine the impact of applying such a restrain on docking, we constructed two semi-flexible protein models by choosing two different crystal structures as reference. Both the balanol analog and ATP were able to dock to either one of these semi-flexible protein models. On the other hand, balanol could only dock well to one of them. Further analysis indicated that the restrain on the glycine-rich loop was too strong, preventing it to adjust its structure to accommodate balanol in the binding pocket of PKA. Removing the restrain on the glycine-rich loop resulted in much better docking poses. This finding demonstrates the important role that the flexibility of the glycine-rich loop play in accepting different ligands and should profitably not be restrained in molecular docking so that more diverse ligands can be studied. Proteins 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

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Substrate phosphorylation by cAMP-dependent-protein kinase A (protein kinase A, PKA) has been studied extensively. Phosphoryl transfer was found to be fast, whereas ADP release was found to be the slow, rate-limiting step. There is also evidence that ADP release may be preceded by a partially rate-limiting conformational change. However, the atomic details of the conformational change and the mode of ADP release are difficult to obtain experimentally. In this work, we studied ADP release from PKA by carrying out molecular dynamics simulations with different pulling forces applied to the ligand. The detailed ADP release pathway and the associated conformational changes were analyzed. The ADP release process was found to involve a swinging motion with the phosphate of ADP anchored to the Gly-rich loop, so that the more buried adenine base and ribose ring came out before the phosphate. In contrast to the common belief that a hinge-bending motion was responsible for the opening of the ligand-binding cleft, our simulations showed that the small lobe exhibited a large amplitude 'rocking' motion when the ligand came out. The largest conformational change of the protein was observed at about the first quarter time point along the release pathway. Two prominent intermediate states were observed in the release process. [ABSTRACT FROM AUTHOR]

AIM AND BACKGROUND: Same-day surgeries are becoming routine for many surgical procedures. However, the degree to which patients need help with pain management at home following laparoscopic cholecystectomy (LC), shoulder, or hand ambulatory day surgery has received minimal examination. This study examined pain and related interference, analgesic use and adverse events, complications and resources utilized, and adequacy of postdischarge information at four time periods. METHODS: Data were collected from 180 patients by telephone interviews at 24, 48 and 72 hours, and 7 days after discharge. Patients (n = 78 hand, 48 shoulder, 54 LC surgery) were on average 41 years old. RESULTS: For all patients, worst 24-hour pain was reported as moderate to severe at all time periods. Using repeated measures anova demonstrated that shoulder patients had significantly more pain and overall pain-related interference, particularly in sleep and work, from 24 hours to day 7 than did hand or LC patients. The main analgesic taken was acetaminophen (paracetamol) with codeine 30 mg; 50% took no analgesia from 72 hours. About 20% experienced analgesic adverse events within 72 hours, mainly constipation and nausea. Only

Helix -capping motifs are believed to play an important role in stabilizing α-helices and defining helix start and stop signals. We performed microsecond scale Brownian dynamics simulations to study ten XAAD sequences, with X = (A,E,I,L,N,Q,S,T,V,Y), to examine their propensity to form helix capping motifs and correlate these results with those obtained from analyzing a structural database of proteins. For the widely studied capping box motif S**D, where the asterisk can be any amino acid residue, the simulations suggested that one of the two hydrogen bonds proposed earlier as a stabilizing factor might not be as important. On the other hand, side-chain interactions between the capping residue and the third residue downstream on the polypeptide chain might also play a role in stabilizing this motif. These results are consistent with explicit-solvent molecular dynamics simulations of two capping box motifs found in the proteins BPTI and α-dendrotoxin. Principal component analysis of the SAAD trajectory showed that the first three principal components, after those corresponding to translational-rotational motion were removed, accounted for more than half of the conformational fluctuations. The first component separated the conformational space into two parts with the all-helical conformation and the capping box motif lying largely in one part. The second component, on the other hand, could be used to describe conformational transitions between the all-helical form and the capping box motif. © 2003 Wiley Periodicals, Inc. Biopolymers 70: 252–259, 2003 [ABSTRACT FROM AUTHOR]

Patients undergoing day surgical procedures are given postoperative instructions not to drink alcohol, drive vehicles or make important decisions for 24 h. They are also advised to have a responsible adult stay with them at home overnight. Seven hundred and fifty patients were telephoned at 24 h postoperatively to determine their compliance with these instructions. Four per cent of patients drove vehicles, 1.8% consumed alcohol, while one patient made an important decision. A higher proportion of patients (5%) drove after general anaesthesia than regional anaesthesia or intravenous sedation (2.4%). The percentage of patients consuming alcohol was similar in both groups (1.8% vs. 1.9%). Four per cent of patients had no one staying with them overnight despite being accompanied out of the hospital. Patient compliance with instructions to not drink alcohol, drive or make important decisions may be improved by physician reinforcement of instructions and patient education. [ABSTRACT FROM AUTHOR]

Background: Anaesthesia comprising remifentanil plus isoflurane, enflurane or propofol was randomly evaluated in 285, 285 and 284 patients, respectively, undergoing short-procedure surgery. Methods: Anaesthesia was induced with propofol (0.5 mg · kg-1 and 10 mg · 10 s-1), and a remifentanil bolus (1 μg · kg-1) and infusion at 0.5 μg · g-1 · min-1. Five minutes after intubation, remifentanil infusion was halved and 0.5 MAC of isoflurane or enflurane, or propofol at 100 μg · kg-1 · min-1 were started and titrated for maintenance. Results: Patient demography and anaesthesia duration were similar between the groups. Surgery was performed as daycases (52%) or inpatients (48%). The median times (5–7 min) to extubation and postoperative recovery were similar between the groups. Responses to tracheal intubation (15% vs 8%) and skin incision (13% vs 7%) were significantly greater in the total intravenous anaesthesia (TIVA) group (P<0.05). Fewer patients given remifentanil and isoflurane (21%) or enflurane (19%) experienced ≥1 intraoperative stress response compared to the TIVA group (28%) (P<0.05). Median times to qualification for and actual recovery room discharge were 0.5–0.6 h and 1.1–1.2 h, respectively. The most common remifentanil-related symptoms were muscle rigidity (6–7%) at induction, hypotension (3–5%) and bradycardia (1–4%) intraoperatively and, shivering (6–7%), nausea and vomiting postoperatively. Nausea (7%) and vomiting (3%) were significantly lower with TIVA compared with inhaled anaesthetic groups (14–15% and 6–8%, respectively; P<0.05). Conclusion: Anaesthesia combining remifentanil with volatile hypnotics or TIVA with propofol was effective and well tolerated. Times of extubation, postanaesthesia recovery and recovery room discharge were rapid, consistent and similar for all three regimens. [ABSTRACT FROM AUTHOR]

Examines the association of postoperative myalgia with the use of succinylcholine. Mechanisms of succinylcholine-induced myalgia; Availability of techniques to prevent and treat the myalgia; Risk of developing myalgia on patients.

Using guinea-pig lung membranes and cloned human β2-receptor adrenergic receptors the effects of whole serum, plasma, purified immunoglobulins and cellular activation products on β2-adrenergic receptor ligand binding and function were investigated. Sera from 24 non-asthmatic subjects and 115 asthmatics in different clinical categories were studied. There were no significant differences between antagonist ([125I] cyanopindolol) inhibition mediated by serum, plasma or by purified IgG when the asthmatics were compared with non-asthmatics. There was also no inhibition of 10-6 M isoproterenol stimulated cAMP release from L cells expressing human β2-adrenergic receptors, by plasma, DEAE purified IgG fractions from asthmatics and non-asthmatics, or by products of activated platelets or lymphocytes. Since we have no evidence that immunoglobulins from asthmatic subjects exert functional inhibition of human β2- adrenergic receptors we conlcude that autoantibodies to the β2-adrenergic receptors do not play an important functional role in the pathophysiology of asthma. [ABSTRACT FROM AUTHOR]