In-silico Inhibitory Study of cFos-cJun Complex by T-5224 Based Small Molecule Analogs

Background:: Inflammatory diseases are one of the major concerns of today’s world, major disorders caused by inflammation includes, allergy, asthma, arthritis, hepatitis, autoimmune diseases, celiac disease etc. During most of these events, many protein and molecules expression were modulated and one such protein is AP-1 (c-Fos-c-Jun heterodimer complex). AP-1 is a dimeric protein activated by several physiological stimuli and environmental insults such as growth factors, polypeptide hormones, neurotransmitters, cytokines, cell-matrix interactions, UV irradiations, viral and bacterial infections. Objective:: Present study is mainly focus on designing of small molecule analogs to inhibit c-Fos-c-Jun complex, as the complex is involved in many inflammatory diseases and precisely involved in disease progression. Therefore, it had been considered as therapeutic target since more than a decade. Methods:: In the present study, an attempt was made to design the analogs of referral drug T-5224. 31 analogs of T-5224 were designed by chemoinformatics approach and subjected to ADMETox for screening. Results and Discussion:: Among the 16 compounds were found to pass the evaluation, all 16 compounds passed the toxicity evaluation except 7th molecule. The molecular docking study showed that the compounds 1, 2 and 16 were having high inhibition constant. Conclusion:: The preliminary results suggest the compounds 1, 2 and 16 are having the potential ligand binding capacity with cFos-cJun complex. Further analysis, with advanced tools, may results in potential small molecule to inhibit the c-Fosc- Jun complex.

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Thalidomide-based inhibitor for TNF-α: designing and Insilico evaluation

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-021-00393-2 ◽

2022 ◽

Vol 8 (1) ◽

Author(s):

Biradar Shivaleela ◽

S. C. Srushti ◽

S. J. Shreedevi ◽

R. L. Babu

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitors ◽

Inflammatory Diseases ◽

Binding Capacity ◽

Preliminary Investigation ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Monocytes And Macrophages ◽

Potential Ligand

Abstract Background Inflammatory diseases are the vast array of disorders caused by inflammation. During most inflammatory events, many cytokines expressions were modulated, and one such cytokine is tumor necrosis factor-alpha (TNF-α). TNF-α is mainly secreted by monocytes and macrophages. Notably, it has been proposed as a therapeutic target for several diseases. The anti-TNF biology approach is mainly based on monoclonal antibodies. The fusion protein and biosimilars are prevalent in treating inflammation for decades. Only a few small molecule inhibitors are available to inhibit the expression of TNF-α, and one such promising drug was thalidomide. Therefore, the study was carried out to design thalidomide-based small molecule inhibitors for TNF-α. The main objective of our study is to design thalidomide analogs to inhibit TNF-α using the insilico approach. Results Several thalidomide analogs were designed using chemsketch. After filtration of compounds through ‘Lipinski rule of 5’ by Molinspiration tool, as a result, five compounds were selected. All these compounds were subjected to molecular docking, and the study showed that all five compounds had good binding energy. However, based on ADMET predictions, two compounds (S3 and S5) were eliminated. Conclusions Our preliminary results suggest that S1, S2, S4 compounds showed potential ligand binding capacity with TNF-α and, interestingly, with limited or no toxicity. Our preliminary investigation and obtained results have fashioned more interest for further in vitro studies.

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Molecular Docking Study of Antibiotics, Anti-Inflammatory Drugs and [Eu(TTA)3⋅AMX] Complex as COVID-19 Biomarker through Interaction of Its Main Protease (Mpro)

Journal of Computational Biophysics and Chemistry ◽

10.1142/s2737416521500216 ◽

2021 ◽

Vol 20 (04) ◽

pp. 405-415

Author(s):

Aluísio Marques da Fonseca ◽

Francisco Aurecio Morais de Araújo ◽

Rubson Mateus Matos Carvalho ◽

Jorge Fernando Silva de Menezes ◽

Andrei Marcelino Sá Pires Silva

Keyword(s):

Bacterial Infections ◽

Genetic Model ◽

Color Change ◽

Uv Light ◽

Scientific Evidence ◽

Docking Study ◽

Molecular Docking Study ◽

Network Parameter ◽

The Neural Network ◽

Main Protease

Coronavirus Acute Respiratory Syndrome (SARS-CoV-2) is a very recent viral infection and has generated one of the world’s biggest problems of all time. There is no scientific evidence and clinical trials to indicate that possible therapies have shown results in suspected or confirmed patients other than the use of immunizations. Given the above, some substances are being studied to be applied to contain their spread and further damage. This work aims to perform an in silico study of amoxicillin, widely known as an antibiotic and used to prevent bacterial infections and a possible biomarker made from a complex with Europium (Eu). It was shown to have the ability to interact with the COVID-19 protein in Mpro protease as ligands. The study was conducted using the AutoDock Vina with Lamarckian genetic model algorithm (GA) combined with the estimation of grid-based energy in rigid and flexible conformation. Compared to affinity energy, amoxicillin presented [Formula: see text][Formula: see text]kcal/mol, which was better than its co-crystallized ligand in the study. The Europium complex, where its synthesis was also demonstrated in this work, presented energy of [Formula: see text][Formula: see text]kcal/mol with hydrogen bonds and possible color change when UV light was applied. For the choice of the best poses in the simulation, the neural network parameter, NNScore2, was used. It can be affirmed that this study is still introductory but promising both in the treatment and identification of the virus.

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Hyaluronan Fragmentation During Inflammatory Pathologies: A Signal that Empowers Tissue Damage

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190906115619 ◽

2020 ◽

Vol 20 (1) ◽

pp. 54-65 ◽

Cited By ~ 3

Author(s):

Angela Avenoso ◽

Giuseppe Bruschetta ◽

Angela D`Ascola ◽

Michele Scuruchi ◽

Giuseppe Mandraffino ◽

...

Keyword(s):

Tissue Injury ◽

Inflammatory Diseases ◽

Biological Effects ◽

Disease States ◽

Cell Matrix ◽

Ecm Degradation ◽

Molecular Sizes ◽

Specific Receptors ◽

Cell Matrix Interactions

: The mechanisms that modulate the response to tissue injury are not fully understood. Abnormalities in the repair response are associated with a variety of chronic disease states characterized by inflammation, followed subsequently by excessive ECM deposition. As cell-matrix interactions are able to regulate cellular homeostasis, modification of ECM integrity appears to be an unspecific factor in promoting the onset and progression of inflammatory diseases. Evidence is emerging to show that endogenous ECM molecules supply signals to damage tissues and cells in order to promote further ECM degradation and inflammation progression. Several investigations have been confirmed that HA fragments of different molecular sizes exhibit different biological effects and responses. In fact, the increased deposition of HA into the ECM is a strong hallmark of inflammation processes. In the context of inflammatory pathologies, highly polymerized HA is broken down into small components, which are able to exacerbate the inflammatory response by inducing the release of various detrimental mediators such as reactive oxygen species, cytokines, chemokines and destructive enzymes and by facilitating the recruitment of leukocytes. However, strategies involving the modulation of the HA fragment with specific receptors on cell surface could represent different promising effects for therapeutic scope. : This review will focus on the inflammation action of small HA fragments in recent years obtained by in vivo reports.

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Identification of potent COVID-19 main protease (MPRO) inhibitors from flavonoids

10.21203/rs.3.rs-34497/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Anita Chauhan ◽

Seema Kalra

Keyword(s):

Drug Target ◽

Binding Capacity ◽

Treatment Options ◽

Docking Study ◽

Binding Energies ◽

Targeted Therapeutics ◽

Molecular Docking Study ◽

Drug Candidates ◽

Main Protease ◽

Target Molecules

Abstract COVID-19 epidemic that commenced in Wuhan in December 2019 has spread worldwide within a few months. Currently, there are no targeted therapeutics and effective treatment options remain very limited. Mpro is a key CoV enzyme, which plays a pivotal role in viral replication and transcription, making it an attractive drug target for this virus. This study was conducted to evaluate the efficacy of flavonoids as drug target molecules against COVID-19 Mpro by molecular docking study. COVID-19 Mpro was docked with 14 flavonoid compounds as well as 4 already existing drugs and the binding energies were determined.Based on the results,we have identified two potential flavonoids with high binding capacity and possible drug candidates. This study will pave a way for doing advanced experimental research to evaluate the real medicinal potential of these compounds to cure COVID-19.

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Spectroscopic, electrochemical and molecular docking study of the binding interaction of a small molecule 5H-naptho[2,1-f][1,2] oxathieaphine 2,2-dioxide with calf thymus DNA

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2017.03.053 ◽

2017 ◽

Vol 101 ◽

pp. 527-535 ◽

Cited By ~ 21

Author(s):

Abhijit Mukherjee ◽

Shovan Mondal ◽

Bula Singh

Keyword(s):

Molecular Docking ◽

Small Molecule ◽

Docking Study ◽

Calf Thymus Dna ◽

Molecular Docking Study ◽

Binding Interaction ◽

Calf Thymus

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3D-QSAR Modeling and Molecular Docking Study on Small Molecule Stat3 Inhibitors, Src Homology 2 Domain Binders

Letters in Drug Design & Discovery ◽

10.2174/1570180813666160801152618 ◽

2016 ◽

Vol 14 (1) ◽

pp. 36-49

Author(s):

Jing Wang ◽

Li Cheng ◽

Yang Quan ◽

Zhen Wang ◽

Fan Wu ◽

...

Keyword(s):

Molecular Docking ◽

Small Molecule ◽

3D Qsar ◽

Docking Study ◽

Molecular Docking Study ◽

Qsar Modeling ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain

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Use of F9 teratocarcinoma STEM cells to study cell-matrix interactions in the early mouse embryo

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100123416 ◽

1992 ◽

Vol 50 (1) ◽

pp. 602-603

Author(s):

Marc Lenburg ◽

Rulang Jiang ◽

Lengya Cheng ◽

Laura Grabel

Keyword(s):

Mouse Embryo ◽

Inner Cell Mass ◽

Cell Mass ◽

Cell Types ◽

Embryoid Bodies ◽

F9 Cells ◽

Cell Matrix ◽

Matrix Interactions ◽

Cell Matrix Interactions ◽

F9 Teratocarcinoma

We are interested in defining the cell-cell and cell-matrix interactions that help direct the differentiation of extraembryonic endoderm in the peri-implantation mouse embryo. At the blastocyst stage the mouse embryo consists of an outer layer of trophectoderm surrounding the fluid-filled blastocoel cavity and an eccentrically located inner cell mass. On the free surface of the inner cell mass, facing the blastocoel cavity, a layer of primitive endoderm forms. Primitive endoderm then generates two distinct cell types; parietal endoderm (PE) which migrates along the inner surface of the trophectoderm and secretes large amounts of basement membrane components as well as tissue-type plasminogen activator (tPA), and visceral endoderm (VE), a columnar epithelial layer characterized by tight junctions, microvilli, and the synthesis and secretion of α-fetoprotein. As these events occur after implantation, we have turned to the F9 teratocarcinoma system as an in vitro model for examining the differentiation of these cell types. When F9 cells are treated in monolayer with retinoic acid plus cyclic-AMP, they differentiate into PE. In contrast, when F9 cells are treated in suspension with retinoic acid, they form embryoid bodies (EBs) which consist of an outer layer of VE and an inner core of undifferentiated stem cells. In addition, we have established that when VE containing embryoid bodies are plated on a fibronectin coated substrate, PE migrates onto the matrix and this interaction is inhibited by RGDS as well as antibodies directed against the β1 integrin subunit. This transition is accompanied by a significant increase in the level of tPA in the PE cells. Thus, the outgrowth system provides a spatially appropriate model for studying the differentiation and migration of PE from a VE precursor.

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