AbstractPhoto‐switchable nuclear receptor modulators (“photohormones”) enable spatial and temporal control over transcription factor activity and are valuable precision tools for biological studies. We have developed a new photohormone chemotype by incorporating a light‐switchable motif in the scaffold of a cinalukast‐derived PPARα ligand and tuned light‐controlled activity by systematic structural variation. An optimized photohormone exhibited PPARα agonism in its light‐induced (Z)‐configuration and strong selectivity over related lipid‐activated transcription factors representing a valuable addition to the collection of light‐controlled tools to study nuclear receptor activity.

13 Aug 2023·Journal of Biomolecular Structure and Dynamics

In-silico discovery of inhibitors against human papillomavirus E1 protein

Article

Author: Hwang, Siaw San ; Rahman, Taufiq ; Wezen, Xavier Chee ; Gunasinghe, Juliyan ; Yam, Wai Keat

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.

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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