Molecular docking and dynamics approach to <i>in silico</i> drug repurposing for inflammatory bowels disease by targeting TNF alpha

Halder, Debojyoti; Das, Subham; Joseph, Alex; Jeyaprakash, R S

doi:10.1080/07391102.2022.2050948

Cited by 21 publications

(13 citation statements)

References 37 publications

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“…In another study, Halder et al [ 105 ] used molecular docking in combination with other in silico techniques for the repurposing of FDA-approved medications and provided a framework for drug exploration and computational methods in the discovery of drugs for the treatment of IBD. After being imported and processed using Protein Preparation Wizard and LigPrep, respectively, the molecular target TNF (protein data bank ID: 2AZ5) with a small molecule inhibitor and the FDA-approved drugs (from the Zinc database) were subjected to molecular docking, ADMET analysis and binding free-energy calculation [Molecular mechanics with generalised Born and surface area solvation (MMGBSA)].…”

Section: Role Of Computational Methods In Ibd Drug Discoverymentioning

confidence: 99%

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Modern drug discovery for inflammatory bowel disease: The role of computational methods

Johnson¹,

Akinsanmi²,

Ejembi³

et al. 2023

World J Gastroenterol

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Inflammatory bowel diseases (IBDs) comprising ulcerative colitis, Crohn’s disease and microscopic colitis are characterized by chronic inflammation of the gastrointestinal tract. IBD has spread around the world and is becoming more prevalent at an alarming rate in developing countries whose societies have become more westernized. Cell therapy, intestinal microecology, apheresis therapy, exosome therapy and small molecules are emerging therapeutic options for IBD. Currently, it is thought that low-molecular-mass substances with good oral bio-availability and the ability to permeate the cell membrane to regulate the action of elements of the inflammatory signaling pathway are effective therapeutic options for the treatment of IBD. Several small molecule inhibitors are being developed as a promising alternative for IBD therapy. The use of highly efficient and time-saving techniques, such as computational methods, is still a viable option for the development of these small molecule drugs. The computer-aided ( in silico ) discovery approach is one drug development technique that has mostly proven efficacy. Computational approaches when combined with traditional drug development methodology dramatically boost the likelihood of drug discovery in a sustainable and cost-effective manner. This review focuses on the modern drug discovery approaches for the design of novel IBD drugs with an emphasis on the role of computational methods. Some computational approaches to IBD genomic studies, target identification, and virtual screening for the discovery of new drugs and in the repurposing of existing drugs are discussed.

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Section: Role Of Computational Methods In Ibd Drug Discoverymentioning

confidence: 99%

“…The MD simulation study was conducted on the two most promising compounds, iopromide (ZINC000003830957) and deferoxamine (ZINC000003830635). Finally, the bioisosteric substitution was applied to enhance the ADMET properties of these compounds[ 105 ].…”

Section: Role Of Computational Methods In Ibd Drug Discoverymentioning

confidence: 99%

Modern drug discovery for inflammatory bowel disease: The role of computational methods

Johnson¹,

Akinsanmi²,

Ejembi³

et al. 2023

World J Gastroenterol

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“…As per some reports, A and B chains were used from PDB: 2AZ5 for computational studies. Therefore A-B chain was used in to dock the peptide into the active site of TNFα [13]- [15]. Similarly, inMD simulation studies, chain A-B from the above structure was used as the peptide was docked into the active site of TNFα [11].…”

Section: Molecular Dynamics (Md) Simulation Analysismentioning

confidence: 99%

Novel Peptide Inhibitor of Human Tumor Necrosis Factor-α has Antiarthritic Activity

Sahu

Gupta

Yennamalli

et al. 2023

Preprint

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The inhibition of tumor necrosis factor-α (TNFα) trimer formation renders it inactive for binding to its receptors thus mitigating the vicious cycle of inflammation. We designed a peptide (PIYLGGVFQ) that simulates a sequence strand of human TNFα monomer using a series of in silico methods, such as active site finding (Acsite), protein-protein interaction (PPI), docking studies (GOLD and Modeller) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNFα. Fluorescence-activated cell sorting (FACS) and fluorescence microscopy revealed that the peptide effectively inhibited the binding of TNF to the cell surface receptors. The cell culture assays showed that the peptide significantly inhibited the TNFα-mediated cell death. In addition, the nuclear translocation of the nuclear factor kappa B (NFκB) was significantly suppressed in the peptide-treated A549 cells as observed in immunofluorescence and gelmobility-shift assays. Furthermore, peptide protected against joint damage in collagen-induced arthritis (CIA)mouse model as revealed in the microfocal-CT scans. In conclusion, this TNFα antagonist would be useful for the prevention and repair ofinflammatory bone destruction and subsequent loss in the mouse model of CIA as well as human rheumatoid arthritis (RA) patients. This calls upon further clinical investigation to utilize its potential effect as an anti-arthritic drug.

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“…Then the energy minimization and equilibration of the prepared system were done. Using an NPT ensemble, the temperature and pressure were set to 300 K and 1.01325 bar, respectively (Halder et al, 2022). The recording interval of the trajectory is 100 ps.…”

Section: Acute Toxicity Studymentioning

confidence: 99%

Synthesis, biological evaluation, and in silico studies of indole‐tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα

Haider

Sharma

Pokharel

et al. 2022

Drug Development Research

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We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a−7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC 50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin.Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dosedependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.

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Molecular docking and dynamics approach to in silico drug repurposing for inflammatory bowels disease by targeting TNF alpha

Cited by 21 publications

References 37 publications

Modern drug discovery for inflammatory bowel disease: The role of computational methods

Modern drug discovery for inflammatory bowel disease: The role of computational methods

Novel Peptide Inhibitor of Human Tumor Necrosis Factor-α has Antiarthritic Activity

Synthesis, biological evaluation, and in silico studies of indole‐tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα

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