Computational Study on Novel Natural Inhibitors Targeting Janus Kinase 3

Abstract Objective: The aim of this study is to screen and identify novel leading compounds 5 which can inhibit protein Janus Kinase 3 (JAK3) from a drug library (ZINC database) 6 to provide precise target therapy for lung cancer. 7Methods: A set of computation-aided structural biology methods and chemical virtual 8 screening techniques were carried out to screen novel inhibitor compounds. Libdock 9 scores for potential inhibitors of JAK3 were calculated using fast docking method-10 virtual screening. Next, ADMET properties (absorption, distribution, metabolism, 11 excretion, and toxicity) were conducted to predict their pharmacological characteristics. 12 The binding affinity as well as the interactions between the candidate compounds and 13 JAK3 were calculated and visualized by precise molecular docking algorithm. 14 Ultimately, molecular dynamics simulation (MD) was performed to estimate the 15 stability of the ligand-JAK3 complex under natural environment. 16Results: After screening, two novel natural compounds, ZINC000014952116 and 17 ZINC00000393864, were finally selected as leading compounds from the ZINC15 18 database, which possessed less Ames mutagenicity, rodent carcinogenicity and 19 developmental toxicity potential than other candidate compounds. Additionally, they 20 didn’t inhibit the activity of CYP2D6. Molecular dynamics simulation analysis showed 21 that ZINC000014952116 and ZINC00000393864 could interact with JAK3 steadily, 22 and their ligand-JAK3 complexes could keep stable under natural situation, and act as 23 regulatory role to JAK3. 24Conclusion: This study analyzed that ZINC000014952116 and ZINC00000393864 25 were ideal natural inhibitors targeting JAK3 from the ZINC15 database, which could 26 also provide more options and resources for other cancer chemotherapy.