Mode-of-Action-Guided, Molecular Modeling-Based Toxicity Prediction: A Novel Approach for In Silico Predictive Toxicology

Aims and Objective: The infectious disease treatment remains a challenging concern owing to the increasing number of pathogenic microorganisms associated with resistance to multiple drugs. A promising approach for combating microbial infection is to combine two or more known bioactive heterocyclic pharmacophores in one molecular platform. Herein, the synthesis and biological evaluation of novel thiazole-thiazolidinone hybrids as potential antimicrobial agents were dissimilated. Materials and Methods: The preparation of the substituted 5-benzylidene-2-thiazolyimino-4- thiazolidinones was achieved in three steps from 2-amino-5-methylthiazoline. All the compounds have been screened in PASS antibacterial activity prediction and in a panel of bacteria and fungi strains. Minimum inhibitory concentration and minimum bacterial concentration were both determined by microdilution assays. Molecular modeling was conducted using Accelrys Discovery Studio 4.0 client. ToxPredict (OPEN TOX) and ProTox were used to estimate the toxicity of the title compounds. Results: PASS prediction revealed the potentiality antibacterial property of the designed thiazolethiazolidinone hybrids. All tested compounds were found to kill and to inhibit the growth of a vast variety of bacteria and fungi, and were more potent than the commercial drugs, streptomycin, ampicillin, bifomazole and ketoconazole. Further, in silico study was carried out for prospective molecular target identification and revealed favorable interaction with the target enzymes E. coli MurB and CYP51B of Aspergillus fumigatus. Toxicity prediction revealed that none of the active compounds was found toxic. Conclusion: Substituted 5-benzylidene-2-thiazolyimino-4-thiazolidinones, endowing remarkable antibacterial and antifungal properties, were identified as a novel class of antimicrobial agents and may find a potential therapeutic use to eradicate infectious diseases.

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Coumarinyl Aryl/Alkyl Sulfonates with Dual Potential: Alkaline Phosphatase and ROS Inhibitory Activities: In-Silico Molecular Modeling and ADME Evaluation

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180327125738 ◽

2019 ◽

Vol 16 (3) ◽

pp. 256-272

Author(s):

Uzma Salar ◽

Khalid Mohammed Khan ◽

Syeda Abida Ejaz ◽

Abdul Hameed ◽

Mariya al-Rashida ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Alkaline Phosphatase ◽

Molecular Modeling ◽

In Silico ◽

Smooth Muscles ◽

Reactive Oxygen ◽

Oxygen Species ◽

Selective Inhibitors ◽

Specific Alkaline Phosphatase ◽

Inhibitory Activities

Background: Alkaline Phosphatase (AP) is a physiologically important metalloenzyme that belongs to a large family of ectonucleotidase enzymes. Over-expression of tissue non-specific alkaline phosphatase has been linked with ectopic calcification including vascular and aortic calcification. In Vascular Smooth Muscles Cells (VSMCs), the high level of Reactive Oxygen Species (ROS) resulted in the up-regulation of TNAP. Accordingly, there is a need to identify highly potent and selective inhibitors of APs for treatment of disorders related to hyper activity of APs. Methods: Herein, a series of coumarinyl alkyl/aryl sulfonates (1-40) with known Reactive Oxygen Species (ROS) inhibition activity, was evaluated for alkaline phosphatase inhibition against human Tissue Non-specific Alkaline Phosphatase (hTNAP) and Intestinal Alkaline Phosphatase (hIAP). Results: With the exception of only two compounds, all other compounds in the series exhibited excellent AP inhibition. For hIAP and hTNAP inhibition, IC50 values were observed in the range 0.62-23.5 µM, and 0.51-21.5 µM, respectively. Levamisole (IC50 = 20.21 ± 1.9 µM) and Lphenylalanine (IC50 = 100.1 ± 3.15 µM) were used as standards for hIAP and hTNAP inhibitory activities, respectively. 4-Substituted coumarinyl sulfonate derivative 23 (IC50 = 0.62 ± 0.02 µM) was found to be the most potent hIAP inhibitor. Another 4-substituted coumarinyl sulfonate derivative 16 (IC50 = 0.51 ± 0.03 µM) was found to be the most active hTNAP inhibitor. Some of the compounds were also found to be highly selective inhibitors of APs. Detailed Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) analysis were carried out to identify structural elements necessary for efficient and selective AP inhibition. Molecular modeling and docking studies were carried out to rationalize the most probable binding site interactions of the inhibitors with the AP enzymes. In order to evaluate drug-likeness of compounds, in silico ADMETox evaluation was carried out, most of the compounds were found to have favorable ADME profiles with good predicted oral bioavailability. X-ray crystal structures of compounds 38 and 39 were also determined. Conclusion: Compounds from this series may serve as lead candidates for future research in order to design even more potent, and selective inhibitors of APs.

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A systematic review of experimental evidence for antiviral effects of ivermectin and an in silico analysis of ivermectin's possible mode of action against SARS‐CoV‐2

Fundamental and Clinical Pharmacology ◽

10.1111/fcp.12644 ◽

2021 ◽

Author(s):

Robert T. Kinobe ◽

Leigh Owens

Keyword(s):

Systematic Review ◽

Experimental Evidence ◽

Mode Of Action ◽

In Silico ◽

In Silico Analysis ◽

Antiviral Effects ◽

Silico Analysis

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IκBα targeting promotes oxidative stress-dependent cell death

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01921-x ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Giovanna Carrà ◽

Giuseppe Ermondi ◽

Chiara Riganti ◽

Luisella Righi ◽

Giulia Caron ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Fate ◽

Protein Interactions ◽

In Silico ◽

Inverse Correlation ◽

Ros Production ◽

Gene Encoding ◽

Specific Expression ◽

Novel Approach ◽

Stress Dependent

Abstract Background Oxidative stress is a hallmark of many cancers. The increment in reactive oxygen species (ROS), resulting from an increased mitochondrial respiration, is the major cause of oxidative stress. Cell fate is known to be intricately linked to the amount of ROS produced. The direct generation of ROS is also one of the mechanisms exploited by common anticancer therapies, such as chemotherapy. Methods We assessed the role of NFKBIA with various approaches, including in silico analyses, RNA-silencing and xenotransplantation. Western blot analyses, immunohistochemistry and RT-qPCR were used to detect the expression of specific proteins and genes. Immunoprecipitation and pull-down experiments were used to evaluate protein-protein interactions. Results Here, by using an in silico approach, following the identification of NFKBIA (the gene encoding IκBα) amplification in various cancers, we described an inverse correlation between IκBα, oxidative metabolism, and ROS production in lung cancer. Furthermore, we showed that novel IκBα targeting compounds combined with cisplatin treatment promote an increase in ROS beyond the tolerated threshold, thus causing death by oxytosis. Conclusions NFKBIA amplification and IκBα overexpression identify a unique cancer subtype associated with specific expression profile and metabolic signatures. Through p65-NFKB regulation, IκBα overexpression favors metabolic rewiring of cancer cells and distinct susceptibility to cisplatin. Lastly, we have developed a novel approach to disrupt IκBα/p65 interaction, restoring p65-mediated apoptotic responses to cisplatin due to mitochondria deregulation and ROS-production.

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Synthesis of bioactive quinoline acting as anticancer agents and their mode of action using in-silico analysis towards Aurora kinase A inhibitors

Chemical Data Collections ◽

10.1016/j.cdc.2021.100768 ◽

2021 ◽

pp. 100768

Author(s):

Kereyagalahally H Narasimhamurthy ◽

Dileep Kumar M. Guruswamy ◽

Chandra ◽

Nichhapurada Kallesha ◽

Basappa ◽

...

Keyword(s):

Anticancer Agents ◽

Mode Of Action ◽

In Silico ◽

In Silico Analysis ◽

Aurora Kinase ◽

Aurora Kinase A ◽

Silico Analysis ◽

Kinase A

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Molecular Modeling Studies on 2,4-Disubstituted Imidazopyridines as Anti-Malarials: Atom-Based 3D-QSAR, Molecular Docking, Virtual Screening, In-Silico ADMET and Theoretical Analysis

Journal of Computational Biophysics and Chemistry ◽

10.1142/s2737416521500125 ◽

2021 ◽

pp. 2150012

Author(s):

Suraj N. Mali ◽

Anima Pandey

Keyword(s):

Molecular Docking ◽

Molecular Modeling ◽

Virtual Screening ◽

In Silico ◽

Energy Gap ◽

3D Qsar ◽

Modeling Studies ◽

In Vitro Investigation ◽

In Silico Admet ◽

Molecular Modeling Studies

Malarial parasites have been reported for moderate-high resistance towards classical antimalarial agents and henceforth development of newer novel chemical entities targeting multiple targets rather than targeting single target will be a highly promising strategy in antimalarial drug discovery. Herein, we carried out molecular modeling studies on 2,4-disubstituted imidazopyridines as anti-hemozoin formation inhibitors by using Schrödinger’s molecular modeling package (2020_4). We have developed statistically robust atom-based 3D-QSAR model (training set, [Formula: see text]; test set, [Formula: see text]; [Formula: see text] [Formula: see text]; root-mean-square error, [Formula: see text]; standard deviation, [Formula: see text]). Our molecular docking, in-silico ADMET analysis showed that dataset molecule 37, has highly promising results. Our ligand-based virtual screening resulted in top five ZINC hits, among them ZINC73737443 hit was observed with lesser energy gap, i.e. 7.85[Formula: see text]eV, higher softness value (0.127[Formula: see text]eV), and comparatively good docking score of [Formula: see text]10.2[Formula: see text]kcal/mol. Our in-silico analysis for a proposed hit, ZINC73737443 showed that this molecule has good ADMET, in-silico nonames toxic as well as noncarcinogenic profile. We believe that further experimental as well as the in-vitro investigation will throw more lights on the identification of ZINC73737443 as a potential antimalarial agent.

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New 3d Multifunctional Metal Chelates of Sulfonamide: Spectral, Vibrational, Molecular Modeling, DFT, Medicinal and In Silico Studies

Journal of Molecular Structure ◽

10.1016/j.molstruc.2021.132305 ◽

2022 ◽

pp. 132305

Author(s):

Abrar Ul Hassan ◽

Sajjad Hussain Sumrra ◽

Muhammad Imran ◽

Zahid Hussain Chohan

Keyword(s):

Molecular Modeling ◽

In Silico ◽

Metal Chelates ◽

In Silico Studies

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Molecular Modeling of Differentially Phosphorylated Serine 10 and Acetylated lysine 9/14 of Histone H3 Regulates their Interactions with 14-3-3ζ, MSK1, and MKP1

Bioinformatics and Biology Insights ◽

10.4137/bbi.s12449 ◽

2013 ◽

Vol 7 ◽

pp. BBI.S12449 ◽

Cited By ~ 7

Author(s):

Ajit K. Sharma ◽

Abhilasha Mansukh ◽

Ashok Varma ◽

Nikhil Gadewal ◽

Sanjay Gupta

Keyword(s):

Molecular Modeling ◽

Protein Kinase ◽

Chromatin Structure ◽

In Silico ◽

Association Studies ◽

Regulatory Proteins ◽

Mitogen Activated Protein Kinase ◽

Site Specific ◽

Mitogen Activated Protein ◽

Neighboring Site

Histone modifications occur in precise patterns, with several modifications known to affect the binding of proteins. These interactions affect the chromatin structure, gene regulation, and cell cycle events. The dual modifications on the H3 tail, serine10 phosphorylation, and lysine14 acetylation (H3Ser10PLys14Ac) are reported to be crucial for interaction with 14-3-3ζ. However, the mechanism by which H3Ser10P along with neighboring site-specific acetylation(s) is targeted by its regulatory proteins, including kinase and phosphatase, is not fully understood. We carried out molecular modeling studies to understand the interaction of 14-3-3ζ, and its regulatory proteins, mitogen-activated protein kinase phosphatase-1 (MKP1), and mitogen- and stress-activated protein kinase-1 (MSK1) with phosphorylated H3Ser10 alone or in combination with acetylated H3Lys9 and Lys14. In silico molecular association studies suggested that acetylated Lys14 and phosphorylated Ser10 of H3 shows the highest binding affinity towards 14-3-3ζ. In addition, acetylation of H3Lys9 along with Ser10PLys14Ac favors the interaction of the phosphatase, MKP1, for dephosphorylation of H3Ser10P. Further, MAP kinase, MSK1 phosphorylates the unmodified H3Ser10 containing N-terminal tail with maximum affinity compared to the N-terminal tail with H3Lys9AcLys14Ac. The data clearly suggest that opposing enzymatic activity of MSK1 and MKP1 corroborates with non-acetylated and acetylated, H3Lys9Lys14, respectively. Our in silico data highlights that site-specific phosphorylation (H3Ser10P) and acetylation (H3Lys9 and H3Lys14) of H3 are essential for the interaction with their regulatory proteins (MKP1, MSK1, and 14-3-3ζ) and plays a major role in the regulation of chromatin structure.

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Design of Improved Anti-Influenza Peptide Mimetics Using In Silico Molecular Modeling

Microbiology & Infectious Diseases ◽

10.33425/2639-9458.1004 ◽

2017 ◽

Vol 1 (1) ◽

Author(s):

Kenneth A. Mwawasi ◽

David C. Bulir ◽

Seiji N. Sugiman-Manrangos ◽

Murray S. Junop ◽

Christopher Stone ◽

...

Keyword(s):

Molecular Modeling ◽

In Silico ◽

Peptide Mimetics

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