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.
Highlights
Cancer drug discovery is a great challenge in recent years
This work focused on the development of anti oral-cancer inhibitor targeting p38a mitogen activated protein kinase (MAPK). p38a has emerged as an attractive target for chemotherapeutic intervention for the treatment of cancer. p38a MAPK is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation, apoptosis and differentiation in a manner that is dependent on the cellular contents
The MAPK cascade presents a new approach for the development of novel cancer therapies intended to be less toxic and provides a valid alternative to conventional chemotherapeutic drugs
Summary
Scientists have learnt a great deal about how faulty genes and proteins contribute to cancer development. This has opened up a new approach for screening the anticancer molecules to enhance the affinity, selectivity (to reduce the potential side effects), efficacy/potency, metabolic stability and oral bioavailability. This work focused on the development of anti oral-cancer inhibitor targeting p38a mitogen activated protein kinase (MAPK). P38a MAPK is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation, apoptosis and differentiation in a manner that is dependent on the cellular contents. Cytokines developed by activating immune cells during chronic inflammation are the major promoters for cancer growth and progression [2,3]. The over production of theses cytokines causes tumor growth or cancer as well as has a critical role in the development and progression of cancer [4]
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