Discovery of Novel Inhibitors of Tumor Necrosis Factor-Alpha and Evaluation their Activity in Rheumatoid Arthritis Patients Using Pharmacophore and Virtual Screening

  • Mohammed Y. Al-Samaree1 Mohammed A. Nadeer2 Faiq 2. Gorial 3, Jalal A. Al-


Tumor Necrosis Factor-alpha (TNFα) is one a pro-inflammatory cytokine which plays a major role in the progress of different autoimmunity diseases such as rheumatoid arthritis (RA) is characterized by chronic arthritis.  Critical cell functions including cell proliferation, survival, differentiation, and apoptosis are regulated by TNFα signals through two transmembrane receptors, TNFR1 and TNFR2. In this study, employed Computer-Aided Drug Design-based (CADD) approach to identify the drug compounds which use in other diseases, and are able to inhibit the TNFα (It was not previously observed as a TNFα inhibitor). search in databases through an online tool “ZINC Pharmer” based on pharmacophore features, PubChem and drug bank. then evaluation of molecular docking-based screening, and the selection of screening ligand complex with TNFα based on Score and root-mean-square deviation (RMSD) value using the Molecular Operating Environment (MOE) system as well as evaluated by the ADMET. Resultantly, three compounds (Mebeverine, Doxazosin and Nebivolol) were identified which showed the highest binding energy with TNFα and a strong inhibitory effect (compare with reference inhibitors). The results of laboratory Evaluation showed that the three compounds produced ΔTm > 2.0 °C and therefore it is indicated as the TNF-alpha hit potential, on the other hand, the values of Kd were (0. 805 μM,0.348 μM and 0.704 μM) and IC50 were (4.29 nM, 4.39 nM, and 2.77 nM) respectively. ΔG has also calculated the values (-8.85 Kcal/ mole), (-8.43 Kcal/ mole) and (-8.44 Kcal/ mole (. The results of (LE) showed a ligand capable of significantly inhibiting TNF-alpha. (LE ≤ 0.3).