Abstract

Osteoarthritis is the fourth leading cause of disability affecting more than 300 million people around the globe. In this disease, chondrocytes responsible for the growth and maintenance of articular joints start to deplete due to the rogue involvement of phosphoinositide 3-kinase, protein kinase-B and p38 mitogenactivated protein kinases. Presently, there are medications providing symptomatic treatment, however, they cannot thwart the progression of osteoarthritis. Natural compounds can rejuvenate injured tissues, averting inflammation and can be useful for treating osteoarthritis. The present study was conducted to obtain inhibitors using natural compounds for phosphoinositide 3-kinase/protein kinase-B/mitogenactivated protein kinases implicated in the pathogenesis of osteoarthritis. Results revealed that out of 1541 natural compounds, cordycepin and geraniol formed an inhibitory interaction with these kinases. Moreover, these compounds down regulated important inflammatory markers (DNA methyltransferase 1, cluster of differentiation 74 and ETS proto-oncogene 1) and increased the expression of glutamate-cysteine ligase catalytic, FAM111 trypsin like peptidase A, secreted frizzled related protein 1 and ferritin light chain genes implicated in the survival of chondrocytes. The absorption, distribution, metabolism, excretion, toxicity and lethal dose prediction studies showed that cordycepin has appropriate pharmacokinetics and low acute toxicity level, whereas geraniol has high toxicity level and efficient pharmacokinetic profile. Our study provided a preliminary insight that cordycepin and geraniol are capable inhibitors of phosphoinositide 3-kinase/protein kinase-B/mitogen-activated protein kinases and can be lead compounds in osteoarthritis therapy.