Abstract
AbstractOsteoarthritis (OA) is an inflammatory disease that primarily impacts the elder population worldwide. Mothers against decapentaplegic homolog 3 (SMAD3), a member of the SMAD family, activates multiple cytokines and suggested as a therapeutic target for OA. SMAD3 variations may affect its protein structure and drug response. This study aimed to screen 195 SMAD3 variants to determine their structural consequences affecting the binding site and affinity of its known inhibitor (SIS‐3). Of these, T261I and R287W are associated with the early onset of OA causing deleterious effects. Molecular docking with SIS‐3 against native (−4.57 kcal mol−1) and variants shows a change in binding affinities (T261I, −5.02 kcal mol−1, and R287W, −4.20 kcal mol−1). Consequently screening 3363 anti‐inflammatory compounds,N‐[[2‐(3,5‐dimethoxyphenyl)‐6‐(trifluoromethyl)pyridin‐3‐yl]methyl]‐2‐[3‐fluoro‐4‐(methanesulfonamido)phenyl]propanamide (N2P) exhibits increased affinity with native (−6.81 kcal mol−1), T261I (−6.91 kcal mol−1), and R287W (−6.90 kcal mol−1) along with MM/GBSA binding energy of −49.20, −50.49, and −50.46 kcal mol−1 than SIS‐3. Further, dynamics simulations reveal conformational stability of N2P with SMAD3 native and variants. The density functional theory confirms the electron transfer capability of N2P in binding with SMAD3 variants. These findings provide insights into structural consequences of SMAD3 variants, improving the understanding of its role in OA and treatment strategies.
Published Version
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