In-silico Inhibitory Study of cFos-cJun Complex by T-5224 Based Small Molecule Analogs

Abstract

Background: Inflammatory diseases are one of the major concerns of today’s world; major disorders caused by inflammation include, allergy, asthma, arthritis, hepatitis, autoimmune diseases, celiac disease, etc. During most of these events, many proteins and molecules expression are modulated and one such protein is AP-1 (c-Fos-c-Jun heterodimer complex). AP-1 is a dimeric protein activated by several physiological stimuli and environmental insults such as growth factors, polypeptide hormones, neurotransmitters, cytokines, cell-matrix interactions, UV irradiations, viral and bacterial infections. Objective: Present study is mainly focused on designing small molecule analogs to inhibit the c- Fos-c-Jun complex, as the complex is involved in many inflammatory diseases and precisely involved in disease progression. Therefore, it had been considered as a therapeutic target for more than a decade. Materials and Methods: In the present study, an attempt was made to design the analogs of referral drug T-5224. 31 analogs of T-5224 were designed by chemoinformatics approach and subjected to ADMETox for screening. Results: Among the 16 compounds that were found to pass the evaluation, all 16 compounds passed the toxicity evaluation except the 7th molecule. The molecular docking study showed that compounds 1, 2 and 16 had high inhibition constant. Conclusion: The preliminary results suggest the compounds 1, 2 and 16 have the potential ligand binding capacity with the cFos-cJun complex. Further analysis, with advanced tools, may result in potential small molecules to inhibit the c-Fos-c-Jun complex.