Leveraging decagonal in-silico strategies for uncovering IL-6 inhibitors with precision.

Autor: Krishna Swaroop A; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamilnadu, India., Krishnan Namboori PK; Amrita Molecular Modeling and Synthesis (AMMAS) Research Lab, Amrita Vishwavidyapeetham, Amrita Nagar, Ettimadai, Coimbatore, Tamilnadu, India., Esakkimuthukumar M; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamilnadu, India., Praveen TK; Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamilnadu, India., Nagarjuna P; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamilnadu, India., Patnaik SK; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamilnadu, India., Selvaraj J; Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Tamilnadu, India. Electronic address: jubie@jssuni.edu.in.
Jazyk: angličtina
Zdroj: Computers in biology and medicine [Comput Biol Med] 2023 Sep; Vol. 163, pp. 107231. Date of Electronic Publication: 2023 Jul 03.
DOI: 10.1016/j.compbiomed.2023.107231
Abstrakt: Interleukin-6 upregulation leads to various acute phase reactions such as local inflammation and systemic inflammation in many diseases like cancer, multiple sclerosis, rheumatoid arthritis, anemia, and Alzheimer's disease stimulating JAK/STAT3, Ras/MAPK, PI3K-PKB/Akt pathogenic pathways. Since no small molecules are available in the market against IL-6 till now, we have designed a class of small bioactive 1,3 - indanedione (IDC) molecules for inhibiting IL-6 using a decagonal approach computational studies. The IL-6 mutations were mapped in the IL-6 protein (PDB ID: 1ALU) from thorough pharmacogenomic and proteomics studies. The protein-drug interaction networking analysis for 2637 FFDA-approved drugs with IL-6 protein using Cytoscape software showed that 14 drugs have prominent interactions with IL-6. Molecular docking studies showed that the designed compound IDC-24 (-11.8 kcal/mol) and methotrexate (-5.20) bound most strongly to the 1ALU south asian population mutated protein. MMGBSA results indicated that IDC-24 (-41.78 kcal/mol) and methotrexate (-36.81 kcal/mol) had the highest binding energy when compared to the standard molecules LMT-28 (-35.87 kcal/mol) and MDL-A (-26.18 kcal/mol). These results we substantiated by the molecular dynamic studies in which the compound IDC-24 and the methotrexate had the highest stability. Further, the MMPBSA computations produced energies of -28 kcal/mol and -14.69 kcal/mol for IDC-24 and LMT-28. KDeep absolute binding affinity computations revealed energies of -5.81 kcal/mol and -4.74 kcal/mol for IDC-24 and LMT-28 respectively. Finally, our decagonal approach established the compound IDC-24 from the designed 1,3-indanedione library and methotrexate from protein drug interaction networking as suitable HITs against IL-6.
Competing Interests: Declaration of competing interest Authors declared no declaration of interest statement.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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