High-risk (HR) Human papillomavirus (e.g. HPV16 and HPV18) causes approximately two-thirds of all cervical cancers in women. Although the first and second-generation vaccines confer some protection against individuals, there are no approved drugs to treat HR-HPV infections to-date. The HPV E1 protein is an attractive drug target because the protein is highly conserved across all HPV types and is crucial for the regulation of viral DNA replication. Hence, we used the Random Forest algorithm to construct a Quantitative-Structure Activity Relationship (QSAR) model to predict the potential inhibitors against the HPV E1 protein. Our QSAR classification model achieved an accuracy of 87.5%, area under the receiver operating characteristic curve of 1.00, and F-measure of 0.87 when evaluated using an external test set. We conducted a drug repurposing campaign by deploying the model to screen the Drugbank database. The top three compounds, namely Cinalukast, Lobeglitazone, and Efatutazone were analyzed for their cell membrane permeability, toxicity, and carcinogenicity. Finally, these three compounds were subjected to molecular docking and 200 ns-long Molecular Dynamics (MD) simulations. The predicted binding free energies for the candidates were calculated using the MM-GBSA method. The binding free energies for Cinalukast, Lobeglitazone, and Efatutazone were -37.84 kcal/mol, -25.30 kcal/mol, and -29.89 kcal/mol respectively. Therefore, we propose their chemical scaffolds for future rational design of E1 inhibitors.Communicated by Ramaswamy H. Sarma.

17 Jul 2019·ChemMedChemQ3 · MEDICINE

Computer‐Assisted Selective Optimization of Side‐Activities—from Cinalukast to a PPARα Modulator

Q3 · MEDICINE

Article

Author: Schierle, Simone ; Kaiser, Astrid ; Pollinger, Julius ; Merk, Daniel ; Ohrndorf, Julia ; Neumann, Sebastian

AbstractAutomated computational analogue design and scoring can speed up hit‐to‐lead optimization and appears particularly promising in selective optimization of side‐activities (SOSA) where possible analogue diversity is confined. Probing this concept, we employed the cysteinyl leukotriene receptor 1 (CysLT1R) antagonist cinalukast as lead for which we discovered peroxisome proliferator‐activated receptor α (PPARα) modulatory activity. We automatically generated a virtual library of close analogues and classified these roughly 8000 compounds for PPARα agonism and CysLT1R antagonism using automated affinity scoring and machine learning. A computationally preferred analogue for SOSA was synthesized, and in vitro characterization indeed revealed a marked activity shift toward enhanced PPARα activation and diminished CysLT1R antagonism. Thereby, this prospective application study highlights the potential of automating SOSA.

01 Nov 2013·Journal of AsthmaQ4 · MEDICINE

A review on leukotrienes and their receptors with reference to asthma

Q4 · MEDICINE

Review

Author: Rakesh Kumar Singh ; Abhijit Ray ; Ruchi Tandon ; Sunanda Ghosh Dastidar

OBJECTIVE AND METHODSLeukotrienes (LTs) including cysteinyl leukotrienes (CysLTs) and LTB4 are the most potent inflammatory lipid mediators and play a central role in the pathophysiology of asthma and other inflammatory diseases. These biological molecules mediate a plethora of contractile and inflammatory responses through specific interaction with distinct G protein-coupled receptors (GPCRs). The main objective of this review is to present an overview of the biological effects of CysLTs and their receptors, along with the current knowledge of mechanisms and role of LTs in the pathogenesis of asthma.RESULTSCysLTs including LTC4, LTD4 and LTE4 are ligands for CysLT1 and CysLT2 receptors, and LTB4 is the agonist for BLT1 and BLT2 receptors. The role of CysLT1 receptor is well established, and most of the pathophysiological effects of CysLTs in asthma are mediated by CysLT1 receptor. Several CysLT1 antagonists have been developed to date and are currently in clinical practice. Most common among them are classical CysLT1 receptor antagonists such as montelukast, zafirlukast, pranlukast, pobilukast, iralukast, cinalukast and MK571. The pharmacological role of CysLT2 receptor, however, is less defined and there is no specific antagonist available so far. The recent demonstration that mice lacking both known CysLT receptors exhibit full/augmented response to CysLT points to the existence of additional subtypes of CysLT receptors. LTB4, on the other hand, is another potent inflammatory leukotriene, which acts as a strong chemoattractant for neutrophils, but weaker for eosinophils. LTB4 is known to play an important role in the development of airway hyper-responsiveness in severe asthma. However there is no LTB4 antagonist available in clinic to date.CONCLUSIONThis review gives a recent update on the LTs including their biosynthesis, biological effects and the role of anti-LTs in the treatment of asthma. It also discusses about the possible existence of additional subtypes of CysLT receptors.

100 Deals associated with Cinalukast

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KEGG	Wiki	ATC	Drug Bank
D02846	Cinalukast	-	DB00587

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	-	F. Hoffmann-La Roche Ltd.	-

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