We report on the development and validation of the OPLS4 force field. OPLS4 builds upon our previous work with OPLS3e to improve model accuracy on challenging regimes of drug-like chemical space that ...includes molecular ions and sulfur-containing moieties. A novel parametrization strategy for charged species, which can be extended to other systems, is introduced. OPLS4 leads to improved accuracy on benchmarks that assess small-molecule solvation and protein–ligand binding.
Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chemical space by addressing limitations in chemotype ...transferability. OPLS3e accomplishes this by incorporating new parameter types that recognize moieties with greater chemical specificity and integrating an on-the-fly parametrization approach to the assignment of partial charges. As a consequence, OPLS3e leads to greater accuracy against performance benchmarks that assess small molecule conformational propensities, solvation, and protein–ligand binding.
Development of the AMOEBA (atomic multipole optimized energetics for biomolecular simulation) force field for proteins is presented. The current version (AMOEBA-2013) utilizes permanent electrostatic ...multipole moments through the quadrupole at each atom, and explicitly treats polarization effects in various chemical and physical environments. The atomic multipole electrostatic parameters for each amino acid residue type are derived from high-level gas phase quantum mechanical calculations via a consistent and extensible protocol. Molecular polarizability is modeled via a Thole-style damped interactive induction model based upon distributed atomic polarizabilities. Inter- and intramolecular polarization is treated in a consistent fashion via the Thole model. The intramolecular polarization model ensures transferability of electrostatic parameters among different conformations, as demonstrated by the agreement between QM and AMOEBA electrostatic potentials, and dipole moments of dipeptides. The backbone and side chain torsional parameters were determined by comparing to gas-phase QM (RI-TRIM MP2/CBS) conformational energies of dipeptides and to statistical distributions from the Protein Data Bank. Molecular dynamics simulations are reported for short peptides in explicit water to examine their conformational properties in solution. Overall the calculated conformational free energies and J-coupling constants are consistent with PDB statistics and experimental NMR results, respectively. In addition, the experimental crystal structures of a number of proteins are well maintained during molecular dynamics (MD) simulation. While further calculations are necessary to fully validate the force field, initial results suggest the AMOEBA polarizable multipole force field is able to describe the structure and energetics of peptides and proteins, in both gas-phase and solution environments.
In a Chinese trial, endovascular thrombectomy at 6 to 24 hours led to more good outcomes than standard care but also to more cerebral hemorrhages. Approximately 20% of patients received intravenous ...thrombolysis.
The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom ...charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein–ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.
The AMOEBA polarizable atomic multipole force field for nucleic acids is presented. Valence and electrostatic parameters were determined from high-level quantum mechanical data, including structures, ...conformational energy, and electrostatic potentials, of nucleotide model compounds. Previously derived parameters for the phosphate group and nucleobases were incorporated. A total of over 35 μs of condensed-phase molecular dynamics simulations of DNA and RNA molecules in aqueous solution and crystal lattice were performed to validate and refine the force field. The solution and/or crystal structures of DNA B-form duplexes, RNA duplexes, and hairpins were captured with an average root-mean-squared deviation from NMR structures below or around 2.0 Å. Structural details, such as base pairing and stacking, sugar puckering, backbone and χ-torsion angles, groove geometries, and crystal packing interfaces, agreed well with NMR and/or X-ray. The interconversion between A- and B-form DNAs was observed in ethanol–water mixtures at 328 K. Crystal lattices of B- and Z-form DNA and A-form RNA were examined with simulations. For the RNA tetraloop, single strand tetramers, and HIV TAR with 29 residues, the simulated conformational states, 3 J-coupling, nuclear Overhauser effect, and residual dipolar coupling data were compared with NMR results. Starting from a totally unstacked/unfolding state, the rCAAU tetranucleotide was folded into A-form-like structures during ∼1 μs molecular dynamics simulations.
Molecular force fields have been approaching a generational transition over the past several years, moving away from well-established and well-tuned, but intrinsically limited, fixed point charge ...models toward more intricate and expensive polarizable models that should allow more accurate description of molecular properties. The recently introduced AMOEBA force field is a leading publicly available example of this next generation of theoretical model, but to date, it has only received relatively limited validation, which we address here. We show that the AMOEBA force field is in fact a significant improvement over fixed charge models for small molecule structural and thermodynamic observables in particular, although further fine-tuning is necessary to describe solvation free energies of drug-like small molecules, dynamical properties away from ambient conditions, and possible improvements in aromatic interactions. State of the art electronic structure calculations reveal generally very good agreement with AMOEBA for demanding problems such as relative conformational energies of the alanine tetrapeptide and isomers of water sulfate complexes. AMOEBA is shown to be especially successful on protein−ligand binding and computational X-ray crystallography where polarization and accurate electrostatics are critical.
BACKGROUND AND PURPOSE—Early use of antiplatelet drugs within 24 hours after intravenous thrombolysis (IVT) has always been a confusing clinical problem. The purpose of this study was to assess the ...safety and efficacy of early low-dose tirofiban treatment in patients with early neurological deterioration (END) within the first 24 hours after IVT.
METHODS—This was a retrospective analysis of prospectively collected data of 1764 consecutive patients with acute ischemic stroke treated with IVT between January 2017 and September 2018. Patients with early neurological deterioration within the first 24 hours after IVT were treated with or without tirofiban. The safety outcomes included symptomatic intracranial hemorrhage, any ICH, severe systemic bleeding, and mortality. Efficacy outcomes included excellent (modified Rankin scale scores 0–1) and favorable (modified Rankin scale scores 0–2) 3-month functional outcomes.
RESULTS—Early neurological deterioration occurred in 278 (15.8%) patients. Of the 187 eligible patients, 121 (64.7%) were treated with tirofiban within the first 24 hours after IVT. Adjusted multivariate analysis showed that early tirofiban use was not associated with symptomatic intracranial hemorrhage (adjusted odds ratio aOR, 1.05; 95% CI, 0.088–11.02; P=1.000), ICH (aOR, 1.13; 95% CI, 0.45–4.25; P=0.512), and mortality (aOR, 0.77; 95% CI, 0.19–2.27; P=0.875) but was significantly associated with excellent (aOR, 2.24; 95% CI, 1.16–3.94; P=0.027) and favorable (aOR, 2.31; 95% CI, 1.48–3.99; P=0.011) functional outcomes. Subgroup analyses suggested that early tirofiban-use efficacy is time dependent, being more effective in patients receiving tirofiban treatment earlier.
CONCLUSIONS—Low-dose tirofiban use in patients with early neurological deterioration within the first 24 hours after IVT did not increase the risk of symptomatic intracranial hemorrhage, ICH, and mortality, it seems associated with neurological improvement at 3 months. Future randomized clinical trials will be needed to validate these results.
Background
In the majority of cases, trigeminal neuralgia (TN) is a unilateral condition with ultra-short stabbing pain located along one or more branches of the trigeminal nerve. Although ...prophylactic pharmacological treatment is first choise, considering of insufficient effect or unacceptable side effects, neurosurgical treatment or lesion treatment should be considered. In addition to all these procedures mentioned above, one approach has been based on local intradermal and/or submucosal injections of Botulinum Toxin Type A (BTX-A).
Methods
We conducted a randomized, double-blind, placebo-controlled since November 2012, and adopted local multi-point injection in 84 cases of classical TN with different doses of BTX-A. Eighty four patients were randomized into following groups: placebo (n = 28); BTX-A 25U (n = 27); BTX-A 75U (n = 29). Follow-up visits were conducted every week after the injection, and the overall duration of the study for each patient were 8 weeks to observe the pain severity, efficacy and adverse reactions at endpoint.
Results
The visual analogue scale (VAS) scores of 25U and 75U groups reduced significantly compared to placebo as early as week 1, and sustained until week 8 throughout the study. There was no significant difference in VAS between 25U and 75U groups throughout the study. The response rates of 25U group (70.4%) and 75U group (86.2%) were significantly higher than placebo group (32.1%) at week 8, and there was no significant difference between 25U and 75U groups. Evaluation of the Patient Global Impression of Change (PGIC) demonstrated that 66.7% (25U group) and 75.9% (75U group) of the patients reported that their pain symptoms were ‘much improved’ or ‘very much improved’ versus 32.1% of the placebo group, and there was also no significant difference between 25U and 75U groups. All adverse reactions were graded as mild or moderate.
Conclusions
BTX-A injection in TN is safe and efficient. It is a useful treatment for refractory TN. Lower dose (25U) and high dose (75U) were similar in efficacy in short-term.
Nearly all stroke neuroprotection modalities, including selective intra-arterial cooling (SI-AC), have failed to be translated from bench to bed side. Potentially overlooked reasons may be biological ...gaps, inadequate attention to reperfusion states and mismatched attention to neurological benefits. To advance stroke translation, we describe a novel thrombus-based stroke model in adult rhesus macaques. Intra-arterial thrombolysis with tissue plasminogen activator leads to three clinically relevant outcomes – complete, partial, and no recanalization based on digital subtraction angiography. We also find reperfusion as a prerequisite for SI-AC-induced benefits, in which models with complete or partial reperfusion exhibit significantly reduced infarct volumes, mitigated neurological deficits, improved upper limb motor dysfunction in both acute and chronic stages; however, no further neuroprotection is observed in those without reperfusion. In summary, we discover reperfusion as a crucial regulator of SI-AC-induced neuroprotection and provide insights of long-term functional benefits in behavior and imaging levels. Our findings could be important not only for the translational prerequisite and potential molecular targets, but also for this thrombus-thrombolysis model in monkeys as a powerful tool for further translational stroke studies.
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