The Pharmacophore Model for the Antistaphylococcal Activity Screening Among Thiazolidinone-Related Structures

The fight against staphylococcal infection, increasing the effectiveness of methods of prevention and treatment of diseases of staphylococcal etiology is of interest to scientists and practitioners, both in Ukraine and around the world. The urgency of this problem is growing rapidly, as there is a tendency to increase the resistance of not only staphylococci, but also other gram-positive bacteria. The spread of methicillin-resistant staphylococci restricts the choice of antibiotics for the treatment of diseases of staphylococcal etiology. Staphylococcus aureus is the most common and dangerous type, which is one of the main factors of purulent-inflammatory lesions of the skin and mucous membranes. As a result of mutations, pathogenic staphylococci acquired resistance to antibacterial drugs. The main disadvantage of modern antibiotics is their non-selectivity. As a result of mutations, pathogenic staphylococci acquired resistance to antibacterial drugs. The main disadvantage of modern antibiotics is their non-selectivity. One of the unique and promising medicinal plants, which contains a rich complex of biologically active substances (BAS), is common hops (Humulus lupulus L.). The complex of BAS (flavonoids, hormones, vitamins, bitter, phenolic compounds, essential oils) causes anti-inflammatory, bactericidal, hyposensitizing and analgesic action of hops. The purpose of this work is to determine the antistaphylococcal activity of the carbon dioxide extract of hops and to justify the development on its basis of new antimicrobial agents for the prevention and treatment of infectious and purulent-inflammatory diseases. The following methods were used: microbiological (method of diffusion into agar (well method)) and mathematical and statistical. The high antimicrobial activity of the carbon dioxide extract of hops has been established for museum test strains of the genus Staphylococcus. The results of the studies testify to the prospects of further study of the bactericidal properties of the extract of hops carbon dioxide with the aim of creating effective antimicrobial agents on its basis for the prevention and treatment of infectious and purulent-inflammatory diseases of staphylococcal etiology.

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Target Fishing of Calactin, Calotropin and Calotoxin Using Reverse Pharmacophore Screening and Consensus Inverse Docking Approach

Current Drug Discovery Technologies ◽

10.2174/1570163817666201207143958 ◽

2020 ◽

Vol 17 ◽

Author(s):

Vikram Parthasarathy ◽

Achuthan Raghava Menon ◽

Basavaraj Devaranavadagi

Keyword(s):

Interleukin 2 ◽

Pharmacophore Model ◽

Positive Control ◽

Screening Strategy ◽

Binding Energies ◽

Cancer Drug ◽

Model Matching ◽

Potential Target ◽

Anti Cancer ◽

Docking Approach

Background: The anticancer properties of natural products calactin, calotropin and calotoxin are well established. However the mechanisms of their action are unclear and the molecular targets pertinent to them are not detailed. In this study, potential anti-cancer targets of these compounds have been identified using reverse screening approaches that may provide valuable insights into anti cancer drug development. Objective: To identify the potential anticancer targets of calactin, calotropin and calotoxin using reverse screening strategy. Methods: The ligands were screened for potential targets based on their shape similarity and pharmacophore model matching. The overlapping targets obtained from both methods were verified using reverse docking approach and validated by docking analysis. MM/PBSA calculation was performed to predict binding affinities between ligand and confirmed targets. Results: Interleukin-2 inducible T cell kinase [ITK] was confirmed as a potential target of calactin (Ki= -10.3 kcal/mol), calotropin (Ki= -8.7 kcal/mol) and calotoxin (Ki= -10.2 kcal/mol). The ligands interacted with hinge region residues such as Met438 and Asp500 which occupy the highly conserved ATP binding site. Binding energies of calactin (∆Ebind = -29.18 kJ/mol), calotropin (-28.57 kJ/mol) and calotoxin (-21.21 kJ/mol) with ITK were higher than (more negative) positive control sunitinib (-15.03 kJ/mol) and standard staurosporine (-21.09 kJ/mol). Besides this, Interstitial collagenase [MMP1] was confirmed as potential target of calotoxin (Ki= -8.2 kcal/mol).However the binding energy (∆Ebind = -11.89 kJ/mol) was lower compared to positive control batimastat (-21.07 kJ/mol). Conclusion: The results of this study confirmed ITK as a potential target for calactin, calotropin and calotoxin. These compounds can therefore be used as lead molecules for the development of novel ITK inhibitors, which may have immense therapeutic applications as immune-suppressants and as anticancer drugs.

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Toward the Identification of Novel Carbonic Anhydrase XIV Inhibitors using 3D-QSAR Pharmacophore Model, Virtual Screening and Molecular Docking Study

Letters in Drug Design & Discovery ◽

10.2174/15701808113106660083 ◽

2014 ◽

Vol 11 (4) ◽

pp. 403-412 ◽

Cited By ~ 1

Author(s):

Tao Liu ◽

Lu Zhou ◽

Taijin Wang ◽

Lufen He ◽

Xiangyang Tang

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Carbonic Anhydrase ◽

Pharmacophore Model ◽

3D Qsar ◽

Docking Study ◽

Molecular Docking Study

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Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180815666181023110736 ◽

2019 ◽

Vol 16 (7) ◽

pp. 775-784

Author(s):

Richa Arya ◽

Satya Prakash Gupta ◽

Sarvesh Paliwal ◽

Swapnil Sharma ◽

Kirtika Madan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Medical Condition ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Docking Studies ◽

Pyridine Derivative ◽

Cleavage Enzyme ◽

Bace 1

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

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DPP-IV Inhibitory Phenanthridines: Ligand, Structure-Based Design and Synthesis

Current Computer - Aided Drug Design ◽

10.2174/1573409915666181211114743 ◽

2020 ◽

Vol 16 (3) ◽

pp. 295-307

Author(s):

Reema A. Khalaf ◽

Dalal Masalha ◽

Dima Sabbah

Keyword(s):

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Ligand Docking ◽

Health Concern ◽

Aromatic Rings ◽

Oral Antidiabetic Agents ◽

Design And Synthesis ◽

Dpp Iv ◽

Novel Scaffold

Background: Lately, diabetes has become the main health concern for millions of people around the world. Dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged as a new class of oral antidiabetic agents. Formerly, acridines, N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives, and sulfamoyl-phenyl acid esters were designed and developed as new DPP-IV inhibitors. Objective: This study aims to develop a pharmacophore model of DPP-IV inhibitors and to evaluate phenanthridines as a novel scaffold for inhibiting DPP-IV enzyme. In addition, to assess their binding interactions with the enzyme through docking in the binding site of 4A5S (PDB). Methods: Herein, Quantum–Polarized Ligand Docking (QPLD) and ligand-based pharmacophore modeling investigations were performed. Three novel 3,8-disubstituted-6-phenyl phenanthridine derivatives 3-5 have been designed, synthesized and characterized. In vitro biological testing against DPP-IV was carried out using fluorometric assay kit. Results: QPLD study demonstrates that compounds 3-5 forms H-bond with Lys554, Trp629, and Tyr631, besides charge transfer interaction between their aromatic rings and the aromatic rings of Tyr547 and Tyr666. Moreover, they fit the three pharmacophoric point features of DPP-IV inhibitors and were proven to have in vitro DPP-IV inhibitory activity where compound 5 displayed a % inhibition of 45.4 at 100 μM concentration. Conclusion: Phenanthridines may serve as a potential lead compound for developing new DPP-IV inhibitors as a promising antidiabetic agent. Computational results suggest future structural simplification.

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Antifungal activity screening for mint and thyme essential oils against Rhizopus stolonifer and their application in postharvest preservation of strawberry and peach fruits

Journal of Applied Microbiology ◽

10.1111/jam.14932 ◽

2020 ◽

Author(s):

J. Yan ◽

H. Wu ◽

F. Shi ◽

H. Wang ◽

K. Chen ◽

...

Keyword(s):

Antifungal Activity ◽

Essential Oils ◽

Rhizopus Stolonifer ◽

Activity Screening

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e-Pharmacophore model-guided design of potential DprE1 inhibitors: synthesis, in vitro antitubercular assay and molecular modelling studies

Chemical Papers ◽

10.1007/s11696-021-01743-3 ◽

2021 ◽

Author(s):

Avinash Kumar ◽

Revathi Rajappan ◽

Suvarna G. Kini ◽

Ekta Rathi ◽

Sriram Dharmarajan ◽

...

Keyword(s):

Pharmacophore Model ◽

Antitubercular Activity ◽

Stable Complex ◽

Dilution Method ◽

Agar Dilution Method ◽

Standard Drug ◽

Docking Score ◽

Mycobacterium Tuberculosis H37rv ◽

Cytotoxicity Studies

AbstractTuberculosis continues to wreak havoc worldwide and caused around 1.4 million deaths in 2019. Hence, in our pursuit of developing novel antitubercular compounds, we are reporting the e-Pharmacophore-based design of DprE1 (decaprenylphosphoryl-ribose 2′-oxidase) inhibitors. In the present work, we have developed a four-feature e-Pharmacophore model based on the receptor–ligand cavity of DprE1 protein (PDB ID 4P8C) and mapped our previous reported library of compounds against it. The compounds were ranked on phase screen score, and the insights obtained from their alignment were used to design some novel compounds. The designed compounds were docked with DprE1 protein in extra-precision mode using Glide module of Maestro, Schrodinger. Some derivatives like B1, B2, B4, B5 and B12 showed comparable docking score (docking score > − 6.0) with respect to the co-crystallized ligand. The designed compounds were synthesized and characterized. In vitro antitubercular activity was carried out on Mycobacterium tuberculosis H37Rv (ATCC27294) strain using the agar dilution method, and minimum inhibitory concentration (MIC) was determined. The compound B12 showed a MIC value of 1.56 μg/ml which was better than the standard drug ethambutol (3.125 μg/ml). Compounds B7 and B11 were found to be equipotent with ethambutol. Cytotoxicity studies against Vero cell lines proved that these compounds were non-cytotoxic. Molecular dynamic simulation study also suggests that compound B12 will form a stable complex with DprE1 protein and will show the crucial H-bond interaction with LYS418 residue. Further in vitro enzyme inhibition studies are required to validate these findings.

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