Target-specific high-throughput screening of anti-inflammatory phytosteroids for autoimmune diseases: A molecular docking-dynamics simulation approach

Abstract

Without proper pathophysiology and recommended therapy, synthetic steroids are widely used as a first-line option for the management of autoimmune diseases. However, their prolonged use often leads to severe side effects such as osteoporosis, hypertension, cardiovascular, gastrointestinal complications, etc. To search for potential and safer therapeutic options, the present study aims to explore the potency and drug-ability profiles of anti-inflammatory phytosteroids (PSs). In a target-specific approach, we have selected three key molecular targets: glucocorticoid receptor/GR (PDB ID: 4P6W), cyclooxygenase-2/COX2 (PDB ID: 5F1A), and inducible nitric oxide synthase/iNOS (PDB ID: 4NOS) for a docking study of 167) selected PSs. The drug-chemistry profiles (physicochemical, toxicity, pharmacokinetic, drug-ability, etc.) of PSs were also assessed using various bioinformatics and chemoinformatics tools. The above assessment suggested that withaminilide B (PS46) is a lead candidate with higher drug-ability properties. Further, the drug stability and kinetic behaviour of the lead with the GR target ‘GR-withaminilide B’ in comparison with the control drug, ‘GR-triamcinolone acetonide’ docking complex, were studied through molecular dynamics (MD) simulation at 200 nanosecond with free energy calculation (MM/PBSA). Overall findings suggested that PSs exhibit distinct drug-ability profiles based on their functional attachments with a steroidal core moiety, where withaminilide B is a lead PSs among all to be used as alternative/ complementary candidates expected with limited adverse effects. Further experimentation is essential before mainstream application, but the study provided a platform to select drug-able candidates with a higher chance of experimental success and accelerate the drug discovery process within limited resources.