Discovery of a Dual-Target Natural Compound for Rheumatoid Arthritis: High-Throughput Screening and Molecular Dynamics of a COX-2/JAK1 Inhibitor

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by recurrent attacks of joints, leading to joint destructive lesions that badly impaired the patients' quality of life. So far, therapies for RA are limited and target single points, such as celecoxib targeting Cyclooxygenase-2 (COX-2) and Tofacitinib targeting Janus Kinase 1 (JAK1), indicating the needs of finding new multilateral therapies with broader targets. Therefore, in the quest to surmount the existing treatments, this work will apply bioactive natural compound screening through high-throughput screening and molecular dynamics simulations, identifying natural product-like dual-activity compounds targeted against the COX-2 and JAK1 enzymes. Out of a total of 3666 natural compounds being screened from the library, through binding affinities and inhibition potentials, there existed superiority over standard drugs for both enzymes. Among them, F3139-1037 came out as a lead compound with favorable physicochemical properties, drug-likeness, and pharmacokinetic and non-toxic profile from the ADME-T analyses. Furthermore, stability within COX-2 and JAK1 active sites was further confirmed by using molecular dynamics simulations, and major stabilizing interactions were pointed out as van der Waals and lipophilic interactions by using MM/GBSA calculations. F3139-1037 is a promising multi-target drug candidate for RA treatment; further investigation of this compound should be performed both in vitro and in vivo. These results form the basis for the development of new, more effective therapies targeting multiple pathways involved in RA.