title: Screening of phytochemicals against protease activated receptor 1 (PAR1), a promising target for cancer.
abstract: BACKGROUND
  Drug resistance and drug-associated toxicity are the primary causes for withdrawal of many drugs, although patient recovery is satisfactory in many instances. Interestingly, the use of phytochemicals in the treatment of cancer as an alternative to synthetic drugs comes with a host of advantages; minimum side effects, good human absorption and low toxicity to normal cells. Protease activated receptor 1 (PAR1) has been established as a promising target in many diseases including various cancers. Strong evidences suggest its role in metastasis also.
  
  
  OBJECTIVE
  There are no natural compounds known to inhibit its activity, so we aimed to identify phytochemicals with antagonist activity against PAR1.
  
  
  METHODS
  We screened phytochemicals from Naturally Occurring Plant-based Anticancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/ ) against PAR1 using virtual screening workflow of Schrödinger software. It analyzes pharmaceutically relevant properties using Qikprop and calculates binding energy using Glide at three accuracy levels (high-throughput virtual screening, standard precision and extra precision).
  
  
  CONCLUSIONS
  Our study led to the identification of phytochemicals, which showed interaction with at least one experimentally determined active site residue of PAR1, showed no violations to Lipinski's rule of five along with predicted high human absorption. Furthermore, structural interaction fingerprint analysis indicated that the residues H255, D256, E260, S344, V257, L258, L262, Y337 and S344 may play an important role in the hydrogen bond interactions of the phytochemicals screened. Of these residues, H255 and L258 residues were experimentally proved to be important for antagonist binding. The residues Y183, L237, L258, L262, F271, L332, L333, Y337, L340, A349, Y350, A352, and Y353 showed maximum hydrophobic interactions with the phytochemicals screened. The results of this work suggest that phytochemicals Reissantins D, 24,25-dihydro-27-desoxywithaferin A, Isoguaiacin, 20-hydroxy-12-deoxyphorbol angelate, etc. could be potential antagonist of PAR1. However, further experimental studies are necessary to validate their antagonistic activity against PAR1.
authors.affiliation: Centre for Biotechnology and Bioinformatics (CBB), School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS) , Secunderabad, Andhra Pradesh , India.
authors.forename: Kavita Kumari
authors.initials: KK
authors.lastname: Kakarala
authors.forename: Kaiser
authors.initials: K
authors.lastname: Jamil
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D064209:Phytochemicals / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D011485:Protein Binding; D044463:Receptor, PAR-1 / Q000235:genetics; D010975:Platelet Aggregation Inhibitors
chemical_list: D064209:Phytochemicals; D044463:Receptor, PAR-1; D010975:Platelet Aggregation Inhibitors
keywords: Docking; Glide; NPACT; Protease activated receptor 1; Qikprop; phytochemicals; virtual screening