DESIGNING A POTENT INHIBITOR FOR HUMAN EIF2AK3 (PERK) - A THERAPEUTIC TARGET FOR PROGRESSIVE SUPRANUCLEAR PALSY

Prashant Kumar* and Satyavani Guttula

ABSTRACT

For a typical drug action, proteins are considered as the major targets as they are the functional molecules in living systems. Conventional laboratory techniques takes minimum ten years in designing a single drug. This time-span is drastically reduced via the use of computational/in-silico tools. Rational designing of a drug starts with finding out the proteins having the potential to be considered as drug targets in disease pathogenesis. Proteomics plays a big role in identification of the same and thus aid in multi-step drug-development process. The process basically comprises of identification and validation of target, selection of lead, molecular screening and optimization, and toxicity testing. This paper aims at designing a computer-assisted, structure based drug of an effective inhibitor of human EIF2AK3 (PERK) gene, a target protein for Progressive Supranuclear Palsy (PSP), a degenerative neurological disorder of uncertain aetiology, caused mainly by mutation of tau gene. Discovery of potent and selective inhibitors which has the potential to inhibit PERK activity in cells and display growth inhibition of human tumour has helped in identifying selective lead compounds as drug candidates. The drug selected via virtual screening and ADME analysis though having a low drug score of 0.27 had no toxicity risks and was good enough for inhibition of the protein expression, so can be used for drug development for further application. The study also provides hints for the future design of new derivatives with higher potency and specificity.

Keywords: Proteomics, Virtual screening, Docking, Drug designing, Drug target.