The interaction of methotrexate with the human C5a and its potential therapeutic implications

Methotrexate (MTX) is an antimetabolite drug that mimics folate and inhibits dihydrofolic acid reductase, resulting in the impairment of malignant growth in actively proliferating tissues. MTX is approved by the FDA for primarily treating non-Hodgkin lymphoma, lymphoblastic leukemia, and osteosarcoma. In addition, MTX is also prescribed as a preferred anti-rheumatic medication for the management of rheumatoid arthritis, including psoriasis, indicating that MTX has a multipronged mechanism of action. MTX is also known to exert anti-inflammatory effects, and interestingly, the role of C5a, a pro-inflammatory glycoprotein of the complement system, is well established in several chronic inflammatory diseases, including rheumatoid arthritis and psoriasis, through the recruitment of C5a receptors (C5aR1/C5aR2) expressed in both immune and non-immune cells. Notably, through drug repurposing studies, we have earlier shown that non-steroidal anti-inflammatory drugs (NSAIDS) can potentially neutralize the function of C5a. Though MTX binds to serum albumin and can affect the immune system, whether its interaction with C5a could be therapeutically beneficial due to the downregulation of both extracellular and intracellular signaling of C5a is not yet established in the literature. In the current study, we have hypothesized and provided preliminary evidence through computational studies that MTX can strongly bind to the hotspot regions on C5a involved in the interactions with its receptors, which is likely to alter the downstream signaling of C5a and contribute to the overall therapeutic efficacy of MTX.