Identification of Natural Compounds as Potential Inhibitors of Likeness, and -23: Virtual Screening, ADMET, Drug -Interleukin Dynamic Simulation

Davood Gheidari ^* Morteza Mehrdad Mahan Etedali

• University of Guilan, Rasht, Iran

Psoriasis is a chronic, immune-mediated condition that affects approximately 100 million individuals worldwide. IL-23 serves as a crucial pro-inflammatory cytokine in the pathogenesis of chronic inflammatory diseases associated with psoriasis. Monoclonal antibody therapies targeting IL-23 inhibit the overactive cytokine signaling that contributes to chronic inflammation across various organ systems.Over the past decade IL-23 inhibitors have gained significant prominence in the treatment of psoriasis. Natural products have emerged as potential modulators of IL-23 activity, particularly in the context of inflammatory diseases such as inflammatory bowel disease (IBD). Several well-characterized phytochemicals, including sulforaphane, resveratrol, and curcumin, have demonstrated efficacy in inhibiting the production and function of Th17 cells, which are regulated by IL-23. However, the exploration of natural products specifically related to psoriasis has been limited. Consequently, this study aimed to identify novel candidates derived from natural products for the treatment of psoriasis. To achieve this, 60,000 natural compounds were filtered according to the Ro5 and obtained from the ZINC database. These compounds underwent high-throughput virtual screening (HTVS) in molecular docking studies against the IL-23 receptor. The top 50 compounds were subsequently re-evaluated using SP,and for enhanced accuracy, the top 19 from the SP protocol were further screened with the XP protocol.The computational screening revealed that the docking energy values for the nineteen ligands binding to the target enzyme ranged from -3.669 to-7.143 kcal/mol. Among these,L1 exhibited the highest binding energy at -7.143 kcal/mol with IL-23. MD simulation further confirmed the stability of the IL-23-L1 complex, highlighting a robust interaction between L1 and the target enzyme, with Tyr100 being one of the amino acids showing the highest frequency of interaction throughout the simulation. DFT analysis using the Becke,3-parameter, Lee-Yang-Parr (B3LYP)/6-31++G(d,p) basis set indicated a promising reactivity profile for the ligands. The analysis of ADMET properties suggested that all inhibitor compounds possess favorable pharmacological characteristics, including appropriate molecular weight, lipophilicity, hydrogen bond donors and acceptors, molecular refractivity, TPSA,and the number of rotatable bonds, all in accordance with Ro5. Additionally, the physicochemical properties indicate that most ligands are capable of HIA and possess a wide therapeutic index, suggesting a favorable safety profile.