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

Swaroop, Akey Krishna; Namboori, P. K. Krishnan; Esakkimuthukumar, M; Krishnamurthy, Praveen Thaggikuppe; Palathoti, Nagarjuna; Patnaik, Sunil Kumar; Selvaraj, Jubie

doi:10.1016/j.compbiomed.2023.107231

Cited by 7 publications

(4 citation statements)

References 52 publications

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“…Similarly, downstream from INF-1 signaling in SSc is increased levels of IL-6 in SSc that ultimately activate nonreceptor tyrosine kinases especially Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins resulting in fibroblast differentiation, proliferation, and ECM and collagen production, providing promising therapeutic targets. 51 , 78 , 79 In line with these observations, tocilizumab, an IL-6 receptor blocker shown to be effective in ILD of SSc, reduces biomarkers of inflammation, ECM turnover, and macrophage activation, including collagen degradation and formation neoepitopes. 80 , 81 Further, there is early evidence that the JAK inhibitors tofacitinib and baricitinib reduce fibrosis in SSc in both lungs and skin, consistent with the known role of JAK/STAT activation in fibrosis in SSc.…”

Section: Autoantibodies As Biomarkers In Sscmentioning

confidence: 73%

Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis

Muruganandam,

Ariza-Hutchinson,

Patel

et al. 2023

JIR

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Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular damage, vasoinstability, and decreased perfusion with ischemia, inflammation, and exuberant fibrosis of the skin and internal organs. Biomarkers are analytic indicators of the biological and disease processes within an individual that can be accurately and reproducibly measured. The field of biomarkers in SSc is complex as recent studies have implicated at least 240 pathways and dysregulated proteins in SSc pathogenesis. Anti-nuclear antibodies (ANA) are classical biomarkers with well-described clinical classifications and are present in more than 90% of SSc patients and include anti-centromere, anti-Th/To, anti-RNA polymerase III, and anti-topoisomerase I antibodies. Transforming growth factor-β (TGF-β) is central to the fibrotic process of SSc and is intimately intertwined with other biomarkers. Tyrosine kinases, interferon-1 signaling, IL-6 signaling, endogenous thrombin, peroxisome proliferator-activated receptors (PPARs), lysophosphatidic acid receptors, and amino acid metabolites are new biomarkers with the potential for developing new therapeutic agents. Other biomarkers implicated in SSc-ILD include signal transducer and activator of transcription 4 (STAT4), CD226 (DNAX accessory molecule 1), interferon regulatory factor 5 (IRF5), interleukin-1 receptor–associated kinase-1 (IRAK1), connective tissue growth factor (CTGF), pyrin domain containing 1 (NLRP1), T-cell surface glycoprotein zeta chain (CD3ζ) or CD247, the NLR family, SP-D (surfactant protein), KL-6, leucine-rich α2-glycoprotein-1 (LRG1), CCL19, genetic factors including DRB1 alleles, the interleukins (IL-1, IL-4, IL-6, IL-8, IL-10 IL-13, IL-16, IL-17, IL-18, IL-22, IL-32, and IL-35), the chemokines CCL (2,3,5,13,20,21,23), CXC (8,9,10,11,16), CX3CL1 (fractalkine), and GDF15. Adiponectin (an indicator of PPAR activation) and maresin 1 are reduced in SSc patients. A new trend has been the use of biomarker panels with combined complex multifactor analysis, machine learning, and artificial intelligence to determine disease activity and response to therapy. The present review is an update of the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

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Section: Autoantibodies As Biomarkers In Sscmentioning

confidence: 73%

Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis

Muruganandam,

Ariza-Hutchinson,

Patel

et al. 2023

JIR

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“…The maximum number of minimization cycles was set at 5,000, with an energy gradient convergence threshold of 0.001 kJ/mol/Å [37,38] . This extensive MD simulation provided valuable insights into the dynamic behaviour and stability of the TC2/5HT4 complex [39,40,41] …”

Section: Molecular Dynamics (Md) Simulationmentioning

confidence: 99%

“…[37,38] This extensive MD simulation provided valuable insights into the dynamic behaviour and stability of the TC2/5HT4 complex. [39,40,41]…”

Section: Compmentioning

confidence: 99%

Computational Evidence for the Anticancer Activity of Phytochemical Constituents of Terminalia Chebula: An In‐Silico Attempt

Dusi,

Saminathan,

Sivakalai

et al. 2024

ChemistrySelect

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Natural compounds represent Secondary metabolites shaped and endorsed by nature over countless years, showcasing both unique chemical variety and a corresponding range of bioactivities, along with drug‐like attributes. Plant‐derived remedies are projected to comprise approximately 25 % of pharmaceuticals in developed nations. Terminalia chebula earns its title as the “King of medicines” due to its multifaceted pharmacological properties. The phytochemical elements within Terminalia chebula were assessed for their interaction with the human dihydrofolate reductase enzyme (5HT4.pdb) due to its significant role in the development of colorectal cancer. The American Cancer Society provides updated CRC statistics based on incidence from population‐based cancer registries and mortality from the National Center for Health Statistics. In 2023, approximately 153,020 individuals will be diagnosed with CRC and 52,550 will die from the disease, including 19,550 cases and 3750 deaths in individuals younger than 50 years. The compounds TC2 (−8.61 Kcal/mol), TC15 (−7.02 Kcal/mol), and TC23 (−6.98 Kcal/mol) demonstrated higher glide scores. Additionally, TC2 (−71.21 Kcal/mol), TC12 (−101.63 Kcal/mol), TC15 (−81.40 Kcal/mol), and TC29 (−77.47 Kcal/mol) exhibited stronger binding affinities (ΔG Bind) to the target. Based on the outcomes of both docking and MM‐GBSA analyses, TC2 was selected for further investigation via molecular dynamics (MD) simulations, which illustrated the stability of the TC2/5HT4 complex. Among the top‐ranked compounds, TC2 adhered to Lipinski's guidelines for drug‐likeness without any violations. Inhibiting the human DHFR enzyme indirectly hampers the progression of colon cancer. The findings from this in‐silico investigation serve as a foundational basis for potential in vitro and in vivo research.

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“…Molecular docking analyses were conducted using PyRx, version 0.8, which seamlessly integrated Vina and AutoDock 4.2 for virtual screening. Leveraging the prepared ligands, refined protein structure, and insights from active site identification, PyRx facilitated the exploration of ligand-protein interactions and prediction of binding conformations with precision and efficiency [12][13][14].…”

Section: Molecular Docking Using Pyrx Version 08mentioning

confidence: 99%

Exploring the Anticonvulsant Properties of a Celecoxib-Phospholipid Conjugate: Synthesis, Activation, and Evaluation of Cytotoxicity

Anjali,

Jawahar,

Praharsh Kumar

et al. 2024

Drug Res (Stuttg)

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Background Epilepsy poses a significant global health challenge, particularly in regions with limited financial resources hindering access to treatment. Recent research highlights neuroinflammation, particularly involving cyclooxygenase-2 (COX-2) pathways, as a promising avenue for epilepsy management. Methods This study aimed to develop a Cyclooxygenase-2 inhibitor with potential anticonvulsant properties. A promising drug candidate was identified and chemically linked with phospholipids through docking analyses. The activation of this prodrug was assessed using phospholipase A2 (PLA2)-mediated hydrolysis studies. The conjugateʼs confirmation and cytotoxicity were evaluated using Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), and Sulphoramide B (SRB) assays. Results Docking studies revealed that the Celecoxib-Phospholipid conjugate exhibited a superior affinity for PLA2 compared to other drug-phospholipid conjugates. FT-IR spectroscopy confirmed the successful synthesis of the conjugate, while DSC analysis confirmed its purity and formation. PLA2-mediated hydrolysis experiments demonstrated selective activation of the prodrug depending on PLA2 concentration. SRB experiments indicated dose-dependent cytotoxic effects of Celecoxib, phospholipid non-toxicity, and efficient celecoxib-phospholipid conjugation. Conclusion This study successfully developed a Celecoxib-phospholipid conjugate with potential anticonvulsant properties. The prodrugʼs specific activation and cytotoxicity profile makes it a promising therapeutic candidate. Further investigation into underlying mechanisms and in vivo studies is necessary to assess its translational potential fully.

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

Cited by 7 publications

References 52 publications

Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis

Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis

Computational Evidence for the Anticancer Activity of Phytochemical Constituents of Terminalia Chebula: An In‐Silico Attempt

Exploring the Anticonvulsant Properties of a Celecoxib-Phospholipid Conjugate: Synthesis, Activation, and Evaluation of Cytotoxicity

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