The design of TOPK inhibitors using structure-based pharmacophore modeling and molecular docking based on an MD-refined homology model

Abstract Numerous inhibitors of tyrosine-protein kinase KIT, a receptor tyrosine kinase, have been explored as a viable therapy for the treatment of gastrointestinal stromal tumor (GIST). However, drug resistance due to acquired mutations in KIT makes these drugs almost useless. The present study was designed to screen the novel inhibitors against the activity of the KIT mutants through pharmacophore modeling and molecular docking. The best two pharmacophore models were established using the KIT mutants’ crystal complexes and were used to screen the new compounds with possible KIT inhibitory activity against both activation loop and ATP-binding mutants. As a result, two compounds were identified as potential candidates from the virtual screening, which satisfied the potential binding capabilities, molecular modeling characteristics, and predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. Further molecular docking simulations showed that two compounds made strong hydrogen bond interaction with different KIT mutant proteins. Our results indicated that pharmacophore models based on the receptor–ligand complex had excellent ability to screen KIT inhibitors, and two compounds may have the potential to develop further as the future KIT inhibitors for GIST treatment.

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Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein

Scientific Reports ◽

10.1038/s41598-021-83626-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Firoz A. Dain Md Opo ◽

Mohammed M. Rahman ◽

Foysal Ahammad ◽

Istiak Ahmed ◽

Mohiuddin Ahmed Bhuiyan ◽

...

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Md Simulation ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Drug Candidate ◽

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein ◽

Apoptosis Process

AbstractX-linked inhibitor of apoptosis protein (XIAP) is a member of inhibitor of apoptosis protein (IAP) family responsible for neutralizing the caspases-3, caspases-7, and caspases-9. Overexpression of the protein decreased the apoptosis process in the cell and resulting development of cancer. Different types of XIAP antagonists are generally used to repair the defective apoptosis process that can eliminate carcinoma from living bodies. The chemically synthesis compounds discovered till now as XIAP inhibitors exhibiting side effects, which is making difficulties during the treatment of chemotherapy. So, the study has design to identifying new natural compounds that are able to induce apoptosis by freeing up caspases and will be low toxic. To identify natural compound, a structure-based pharmacophore model to the protein active site cavity was generated following by virtual screening, molecular docking and molecular dynamics (MD) simulation. Initially, seven hit compounds were retrieved and based on molecular docking approach four compounds has chosen for further evaluation. To confirm stability of the selected drug candidate to the target protein the MD simulation approach were employed, which confirmed stability of the three compounds. Based on the finding, three newly obtained compounds namely Caucasicoside A (ZINC77257307), Polygalaxanthone III (ZINC247950187), and MCULE-9896837409 (ZINC107434573) may serve as lead compounds to fight against the treatment of XIAP related cancer, although further evaluation through wet lab is necessary to measure the efficacy of the compounds.

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In silico studies on novel inhibitors of MERS-CoV: Structure-based pharmacophore modeling, database screening and molecular docking

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v17i3.18 ◽

2018 ◽

Vol 17 (3) ◽

pp. 513 ◽

Cited By ~ 1

Author(s):

Awwad A. Radwan ◽

Fares K. Alanazi

Keyword(s):

Molecular Docking ◽

In Silico ◽

Pharmacophore Modeling ◽

Database Screening

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Design, Synthesis, and In Vivo and In Silico Evaluation of Coumarin Derivatives with Potential Antidepressant Effects

Molecules ◽

10.3390/molecules26185556 ◽

2021 ◽

Vol 26 (18) ◽

pp. 5556

Author(s):

Xuekun Wang ◽

Hao Zhou ◽

Xinyu Wang ◽

Kang Lei ◽

Shiben Wang

Keyword(s):

Molecular Docking ◽

High Resolution Mass Spectrometry ◽

Forced Swim Test ◽

Antidepressant Activity ◽

Tail Suspension Test ◽

Homology Model ◽

Coumarin Derivatives ◽

Monitoring Methods ◽

Discovery Studio

In this study, a series of coumarin derivatives were designed and synthesized, their structures were characterized using nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) testing methods. In the pharmacological experiment, two behavior-monitoring methods, the forced swim test (FST) and the tail suspension test (TST), were used to determine the antidepressant activity of coumarin derivatives. Compounds that showed potential activity were analyzed for their effects on 5-hydroxytryptamine (5-HT) levels in the brains of mice. Molecular docking experiments to simulate the possible interaction of these compounds with the 5-HT1A receptor was also be predicted. The results of the pharmacological experiments showed that most coumarin derivatives exhibited significant antidepressant activity. Among these compounds, 7-(2-(4-(4-fluorobenzyl)piperazin-1-yl)-2-oxoethoxy)-2H-chromen-2-one (6i) showed the highest antidepressant activity. The results of the measurement of 5-HT levels in the brains of mice indicate that the antidepressant activity of coumarin derivatives may be mediated by elevated 5-HT levels. The results of molecular docking demonstrated that compound 6i had a significant interaction with amino acids around the active site of the 5-HT1A receptor in the homology model. The physicochemical and pharmacokinetic properties of the target compounds were also predicted using Discovery Studio (DS) 2020 and Chemdraw 14.0.

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STRUCTURE-BASED MULTITARGETED MOLECULAR DOCKING ANALYSIS OF PYRAZOLE-CONDENSED HETEROCYCLICS AGAINST LUNG CANCER

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2021v13i6.42801 ◽

2021 ◽

pp. 157-169

Author(s):

JAINEY P. JAMES ◽

AISWARYA T. C. ◽

SNEH PRIYA ◽

DIVYA JYOTHI ◽

SHESHAGIRI R. DIXIT

Keyword(s):

Lung Cancer ◽

Molecular Docking ◽

Binding Mode ◽

Pharmacophore Modeling ◽

In Vivo Studies ◽

Spectral Studies ◽

Pyrazole Derivatives ◽

Anticancer Activities

Objective: The significant drawbacks of chemotherapy are that it destroys healthy cells, resulting in adverse effects. Hence, there is a need to adopt new techniques to develop cancer-specific chemicals that target the molecular pathways in a non-toxic fashion. This study aims to screen pyrazole-condensed heterocyclics for their anticancer activities and analyse their enzyme inhibitory potentials EGFR, ALK, VEGFR and TNKS receptors. Methods: The structures of the compounds were confirmed by IR, NMR and Mass spectral studies. The in silico techniques applied in this study were molecular docking and pharmacophore modeling to analyse the protein-ligand interactions, as they have a significant role in drug discovery. Drug-likeness properties were assessed by the Lipinski rule of five and ADMET properties. Anticancer activity was performed by in vitro MTT assay on lung cancer cell lines. Results: The results confirm that all the synthesised pyrazole derivatives interacted well with the selected targets showing docking scores above-5 kcal/mol. Pyrazole 2e interacted well with all the four lung cancer targets with its stable binding mode and was found to be potent as per the in vitro reports, followed by compounds 3d and 2d. Pharmacophore modeling exposed the responsible features responsible for the anticancer action. ADMET properties reported that all the compounds were found to have properties within the standard limit. The activity spectra of the pyrazoles predicted that pyrazolopyridines (2a-2e) are more effective against specific receptors such as EGFR, ALK and Tankyrase. Conclusion: Thus, this study suggests that the synthesised pyrazole derivatives can be further investigated to validate their enzyme inhibitory potentials by in vivo studies.

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