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

小分子 化学 甲氨蝶呤 人口 生物信息学 药理学 类风湿性关节炎 计算生物学 生物信息学 医学 生物化学 生物 免疫学 基因 环境卫生
作者
Akey Krishna Swaroop,P. K. Krishnan Namboori,M. Esakkimuthukumar,Praveen Thaggikuppe Krishnamurthy,Nagarjuna Palathoti,Sunil Kumar Patnaik,Jubie Selvaraj
出处
期刊:Computers in Biology and Medicine [Elsevier BV]
卷期号:163: 107231-107231 被引量:9
标识
DOI:10.1016/j.compbiomed.2023.107231
摘要

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.
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