MOLECULAR DOCKING AND ADMET ANALYSIS OF NATURAL PHYTOCONSTITUENTS ON TOLL-LIKE RECEPTOR – 4 AND NOD-LIKE RECEPTOR – 3 INHIBITORS USED FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

Rheumatoid arthritis (RA) causes joint disability due to pannus formation, synovitis, joint erosion, joint destruction and cartilage damage. Disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs) prevent the disease progression but suffer the disadvantage of severe adverse drug reactions. An extensive literature search revealed reports of 176 phytoconstituents having anti-inflammatory and/or anti-arthritic activity. Their binding affinities to TLR-4 and NLRP3 receptors were predicted by molecular docking using target proteins of TLR4-MD2 (PDB ID: 3FXI) and chain A and chain B of NLRP3 (PDB ID: 6NPY). Docking score results revealed that 11 phytoconstituents with promising inhibition of TLR4-MD2 along with 27 phytoconstituents inhibiting binding to Chain A of NLRP3 and 65 phytoconstituents binding to Chain B of NLRP3 proteins were identified through an extra precision (XP) docking study by comparing standard antagonists of TLR4 such as Resatorvid and standard antagonists of NLRP3, i.e., MCC950 and Anakinra. Further, we analyzed the pharmacokinetic properties (absorption, distribution, metabolism, excretion, and toxicity) of selected phytoconstituents using pKCSM. Thus, this study reveals that the selected phytoconstituents could have promising anti-inflammatory and antiarthritic activity in rheumatoid arthritis.