title: The rational design of specific peptide inhibitor against p38α MAPK at allosteric-site: a therapeutic modality for HNSCC.
abstract: p38α is a significant target for drug designing against cancer. The overproduction of p38α MAPK promotes tumorigenesis in head and neck squamous cell carcinoma (HNSCC). The ATP binding and an allosteric site referred as DFG are the key sites of the p38α mitogen activated protein kinase (MAPK) exploited for the design of inhibitors. This study demonstrated design of peptide inhibitor on the basis of allosteric site using Glide molecular docking software and the biochemical analysis of the best modeled peptide. The best fitted tetrapeptide (FWCS) in the allosteric site inhibited the pure recombinant and serum p38α of HNSCC patients by 74 and 72%, respectively. The potency of the peptide was demonstrated by its IC50 (4.6 nM) and KD (3.41×10-10 M) values, determined by ELISA and by surface plasmon resonance (SPR) technology, respectively. The cell viability of oral cancer i.e. KB cell line was reduced in dose dependent manner by 60 and 97% by the treatment of peptide and the IC50 was 600 and 210 µM after 24 and 72 h incubation, respectively. Our result provides an insight for the development of a proficient small peptide as a promising anticancer agent targeting DFG site of p38α kinase.
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Kamaldeep
authors.initials: K
authors.lastname: Gill
authors.affiliation: School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Nigam
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Ratnakar
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Naidu
authors.initials: N
authors.lastname: Subbarao
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Shyam Singh
authors.initials: SS
authors.lastname: Chauhan
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Dey
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010455:Peptides; D048308:Mitogen-Activated Protein Kinase 14