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Abstract: Aim: The aim was to evaluate the beneficial effect of early mitogen‐activated protein kinase (MEK)1/2 inhibition administered at a clinical relevant time‐point using the transient middle cerebral artery occlusion model and a dedicated rodent magnetic resonance imaging system (9.4T) to monitor cerebrovascular changes non‐invasively for 2 weeks. Method: Transient middle cerebral artery occlusion was induced in male rats for two hours followed by reperfusion. The specific MEK1/2 inhibitor U0126 was administered ip at 6 and 24 hours post‐reperfusion. Neurological functions were evaluated by 6‐ and 28‐point tests. 9.4 T magnetic resonance imaging was used to monitor morphological infarct changes at day 2, 8 and 14 after stroke and to evaluate cerebral perfusion at day 14. Immunohistochemistry evaluation of Ki67 was performed 14 days post‐stroke. Results: U0126 improved long‐term behavioural outcome and significantly reduced infarct size. In addition, cerebral perfusion in U0126‐treated animals was improved compared to the vehicle group. Immunohistochemistry showed a significant increase in Ki67+ cells in U0126‐treated animals compared to the vehicle group. Conclusion: Early MEK1/2 inhibition improves long‐term functional outcome, promotes recovery processes after stroke and most importantly provides a realistic time window for therapy. [ABSTRACT FROM AUTHOR]

Aim Extracellular signal-regulated kinase ( ERK) 1/2 is activated during acute phase of stroke and contributes to stroke pathology. We have found that acute treatment with MEK1/2 inhibitors decreases infarct size and neurological deficits 2 days after experimental stroke. However, it is not known whether benefits of this inhibition persist long-term. Therefore, the aim of this study was to assess neurological function, infarct size and recovery processes 14 days after stroke in male rats to determine long-term outcome following acute treatment with the MEK1/2 inhibitor U0126. Methods Transient middle cerebral artery occlusion was induced in male rats. U0126 or vehicle was given at 0 and 24 h of reperfusion. Neurological function was assessed by staircase, 6-point and 28-point neuroscore tests up to 14 days after induction of stroke. At day 14, infarct volumes were determined and recovery processes were evaluated by measuring protein expression of the tyrosine kinase receptor Tie-2 and nestin. Levels of p- ERK1/2 protein were determined. Results Acute treatment with U0126 significantly improved long-term functional recovery, reduced infarct size, and enhanced Tie-2 and nestin protein expression at 14 days post-stroke. There was no residual blockade of p- ERK1/2 at this time point. Conclusion It is demonstrated that benefits of early treatment with U0126 persist beyond subacute phase of ischaemic stroke in male rats. Prevention of ERK1/2 activation in the acute phase results in improved long-term functional outcome and enhances later-stage recovery processes. These results expand our understanding of the benefits and promise of using MEK1/2 inhibitors in stroke recovery. [ABSTRACT FROM AUTHOR]

Kinases are key targets for many of the pathological conditions. Inverse screening of ligands serves as an essential mode to identify potential kinase targets in modern drug discovery research. Hence, we intend to develop KinomeRun, a robust pipeline for inverse screening and kinome tree visualization through the seamless integration of kinome structures, docking and kinome-drug interaction fingerprint analysis. In this pipeline, the hurdle of residue numbering in kinome is also resolved by creating a common index file with the conserved kinase pocket residues for comparative interaction analysis. KinomeRun can be used to screen the ligands of interest docked against multiple kinase structures in parallel around the kinase binding site and also to filter out the targets with unique interaction patterns. This automation is essential for prioritization of kinase targets that show specificity for a given drug and will also serve as a crucial tool kit for holistic approaches in kinase drug discovery. KinomeRun is developed using python and bash programming language and is distributed freely under the GNU GPL licence-3.0 and can be downloaded at https://github.com/inpacdb/KinomeRun. The tutorial videos for installation, target screening and customized filtration are available at https://www.youtube.com/playlist?list=PLuIaEFtMVgQ7v__WigQH9ilGVxrfI1LKs and also be downloaded for offline viewing from the github link., (© 2020 John Wiley & Sons A/S.)

Peptide therapeutics is proven to be highly potential in the treatment of various diseases due to its specificity, biological safety, and cost-effectiveness. Many of the FDA-approved peptides are currently available for therapeutic applications. In the current postgenomic era, high-throughput computational screening of drugs and peptides are highly exploited in peptide therapeutics for cost-effective and robustness. However, there is a paucity of efficient pipelines that automate virtual screening process of peptides through integration of open-source tools that are optimal to perform ensemble and flexible docking protocols. Hence, in this study, we developed a GUI-based pipeline named PepVis for automated script generation for large-scale peptide modeling and virtual screening. PepVis integrates Modpep and Gromacs for peptide structure modeling and optimization; AutoDock Vina, ZDOCK, and AutoDock CrankPep for virtual screening of peptides; ZRANK2 for rescoring of protein-peptide complexes, and FlexPepDock for flexible refinement of protein-peptide complexes. Benchmarking of ensemble docking through PepVis infers that ModPep + Vina to outperform ModPep + ZDock in terms of detecting near-natives from LEADS-PEP dataset. PepVis is built modular to incorporate many other docking algorithms in the future. This pipeline is distributed freely under the GNU GPL license and can be downloaded at https://github.com/inpacdb/PepVis., (© 2019 John Wiley & Sons A/S.)