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

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.

Targeting of ErbB1, ErbB2, and their Dual Targeting Using Small Molecules and Natural Peptides: Blocking EGFR Cell Signaling Pathways in Cancer: A Mini-Review.

Cancer is one of the deadliest diseases involving dysregulated cell proliferation and has been the leading cause of death worldwide. The chemotherapeutic drugs currently used for treating cancer have serious drawbacks of non-specific toxicity and drug resistance. The four members of the human epidermal growth factor receptor (EGFR), namely, ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4, the trans-membrane family of tyrosine kinase receptors, are overexpressed in many types of cancers. These receptors play an important role in cell proliferation, differentiation, invasion, metastasis and angiogenesis and unregulated activation of cancer cells. Overexpression of ErbB1 and ErbB2 occurs in several types of cancers and is associated with a poor prognosis leading to resistance to ErbB1 directed therapies. Heterodimerization with ErbB2/HER2 is a potent activator of Epidermal Growth Factor Receptor-Tyrosine kinase (EGFRTK) complex than EGFR alone. Though ErbB3/HER3 can bind to a ligand, its kinase domain is devoid of catalytic activity and hence relies on its partner (ErbB2/HER2) for initiation of signals, thus, ErbB2 is involved in the activation of ErbB3. However, recent evidence reveals that ErbB1 and ErbB2 are the most important targets for cancer therapy. By inhibiting these two important kinases, the cancer cell signaling transduction pathways can be inhibited. Lapatinib and monoclonal antibodies like trastuzumab have been used for the dual inhibition of ErbB1 and ErbB2 in the treatment of various cancers. Resistance, however, develops soon. The present report reviews the investigations that have been carried out by earlier workers for targeting ErbB1, ErbB2, and both using small molecules and novel peptides that could help/facilitate researchers to design and develop better cancer chemotherapy.