Structure and putative signaling mechanism of Protease activated receptor 2 (PAR2) – A promising target for breast cancer

Kakarala, Kavita Kumari; Jamil, Kaiser; Devaraji, Vinod

doi:10.1016/j.jmgm.2014.07.012

Cited by 25 publications

(15 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lately, investigators tried to study GPCR-ligand interactions utilizing template based homology models. 16 In fact, there have been some recent studies where researchers have modeled the structure of PAR-2 using various templates and screened compounds based on them. 17,18 However, the validation of these models and the authenticity of the "hits" is always questionable owing to the concerns arising from low-sequence homology models.…”

Section: Discussionmentioning

confidence: 99%

Drug repositioning as an effective therapy for protease‐activated receptor 2 inhibition

Saqib

Savai

Liu

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

Proteinase‐activated receptor 2 (PAR‐2) is a G protein–coupled receptor activated by both trypsin and a specific agonist peptide, SLIGKV‐NH2. It has been linked to various pathologies, including pain and inflammation. Several peptide and peptidomimetic agonizts for PAR‐2 have been developed exhibiting high potency and efficacy. However, the number of PAR‐2 antagonists is smaller. We screened the Food and Drug Administration library of approved compounds to retrieve novel antagonists for repositioning in the PAR‐2 structure. The most efficacious compound bicalutamide bound to the PAR‐2 binding groove near the extracellular domain as observed in the in silico studies. Further, it showed reduced Ca2+ release in trypsin activated cells in a dose‐dependent manner. Hence, bicalutamide is a novel and potent PAR‐2 antagonist which could be therapeutically useful in blocking multiple pathways diverging from PAR‐2 signaling. Further, the novel scaffold of bicalutamide represents a new molecular structure for PAR‐2 antagonism and can serve as a basis for further drug development.

show abstract

Section: Discussionmentioning

confidence: 99%

Drug repositioning as an effective therapy for protease‐activated receptor 2 inhibition

Saqib

Savai

Liu

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…The phytochemicals with proven antibacterial, antifungal, antiprotozoal, and antiviral activities were selected from the database of Potential "Antibiotics" from flowering plants developed ( Protein preparation PAR2 homology model was obtained using methodology published by our group recently (Kakarala, Jamil, & Devaraji, 2014). The homology model of PAR2 was prepared using protein preparation wizard of Schrödinger (Schrödinger Suite 2012 Protein Preparation Wizard;Epik version 2.3, Schrödinger, LLC, New York, NY, 2012;Impact version 5.8, Schrödinger, LLC, New York, NY, 2012;Prime version 3.1, Schrödinger, LLC, New York, NY, 2012).…”

Section: Methodsmentioning

confidence: 99%

“…The numbers within brackets in the following sections indicate the Ballesteros-Weinstein numbering (Ballesteros, Weinstein, & Stuart, 1995) and the numbering of residues corresponds to the number assigned by Schrödinger software as described in our recent publication (Kakarala et al, 2014).…”

Section: Number System Of Amino Acidsmentioning

confidence: 99%

Protease activated receptor-2 (PAR2): possible target of phytochemicals

Kakarala

Jamil

2014

Journal of Biomolecular Structure and Dynamics

Self Cite

View full text Add to dashboard Cite

The use of phytochemicals either singly or in combination with other anticancer drugs comes with an advantage of less toxicity and minimal side effects. Signaling pathways play central role in cell cycle, cell growth, metabolism, etc. Thus, the identification of phytochemicals with promising antagonistic effect on the receptor/s playing key role in single transduction may have better therapeutic application. With this background, phytochemicals were screened against protease-activated receptor 2 (PAR2). PAR2 belongs to the superfamily of GPCRs and is an important target for breast cancer. Using in silico methods, this study was able to identify the phytochemicals with promising binding affinity suggesting their therapeutic potential in the treatment of breast cancer. The findings from this study acquires importance as the information on the possible agonists and antagonists of PAR2 is limited due its unique mechanism of activation.

show abstract

“…The identified 23 compounds were prepared using the Maestro molecular modelling LigPrep module [33] with the OPLS-2005 forcefield [34]. An issue to be considered is the ionization of the ligand in physiological environments.…”

Section: Ligand Preparationmentioning

confidence: 99%

Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors

Şahin

Durdağı

2020

Turk J Chem

View full text Add to dashboard Cite

The excessive activity of acetylcholinesterase enzyme (AChE) causes different neuronal problems, especially dementia and neuronal cell deaths. Food and Drug Administration (FDA) approved drugs donepezil, rivastigmine, tacrine and galantamine are AChE inhibitors and in the treatment of Alzheimer’s disease (AD) these drugs are currently prescribed. However, these inhibitors have various adverse side effects. Therefore, there is a great need for the novel selective AChE inhibitors with fewer adverse side effects for the effective treatment. In this study, combined ligand-based and structure-based virtual screening approaches were used to identify new hit compounds from small molecules library of National Cancer Institute (NCI) containing approximately 265,000 small molecules. In the present study, we developed a computational pipeline method to predict the binding affinities of the studied compounds at the specific target sites. For this purpose, a text mining study was carried out initially and compounds containing the keyword “indol” were considered. The therapeutic activity values against AD were screened using the binary quantitative structure activity relationship (QSAR) models. We then performed docking, molecular dynamics (MD) simulations and free energy analysis to clarify the interactions between selected ligands and enzyme. Thus, in this study we identified new promising hit compounds from a large database that may be used to inhibit the enzyme activity of AChE.

show abstract

Structure and putative signaling mechanism of Protease activated receptor 2 (PAR2) – A promising target for breast cancer

Cited by 25 publications

References 112 publications

Drug repositioning as an effective therapy for protease‐activated receptor 2 inhibition

Drug repositioning as an effective therapy for protease‐activated receptor 2 inhibition

Protease activated receptor-2 (PAR2): possible target of phytochemicals

Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors

Contact Info

Product

Resources

About