scholarly journals In SilicoScreening of the Library of Pyrimidine Derivatives as Thymidylate Synthase Inhibitors for Anticancer Activity

2009 ◽  
Vol 6 (3) ◽  
pp. 665-672 ◽  
Author(s):  
A. G. Nerkar ◽  
S. A. Ghone ◽  
A. K. Thaker
Keyword(s):  
Thymidylate Synthase ◽  
In Silico ◽  
Active Metabolite ◽  
Heterocyclic Ring ◽  
Pyrimidine Derivatives ◽  
Structural Modifications ◽  
Pharmacokinetic Properties ◽  
Adme Properties ◽  
Thymidylate Synthase Inhibitors ◽  
Potential Inhibitors

We here report the virtual screening of several series of pyrimidine derivatives forin silicoThymidylate Synthase (TS) inhibition to arrive at possible potential inhibitors of TS with acceptable pharmacokinetic or ADME (Absorption, Distribution, Metabolism and Excretion) properties. Library of the molecules was constructed based upon structural modifications of pyrimidines nucleus. Structural modifications in descending order were performed for the series of pyrimidines,vizfrom pyrimidines with five membered heterocyclic ring to pyrimidines with four membered heterocyclic ring to simple pyrimindine carboxylates in an order to arrive at pyrimidines with better inhibition scores (G-Scores) as compared with Raltitrexed (RTX) and active metabolite of 5-Fluorouracil (5-FUMP). The molecules with betterG-Scores were subjected to predict pharmacokinetic or ADME properties. The molecules with acceptable ADME properties and betterG-Scores were prioritized for synthesis and anticancer evaluation. Three molecules from pyrimidine carboxylate series PIC1-31were found acceptable withG-Scores and pharmacokinetic properties. Thus a library of pyrimidine derivatives was constructed based upon the feasibility of synthesis and in silico screened to prioritize the molecules and to obtain potential lead molecules as TS inhibitors.

In Silico Investigation: Opening Doors to Novel Thymidylate Synthase Inhibitors

2020 ◽  
Vol 16 (3) ◽  
pp. 224-237
Author(s):  
Sheenu Mittal ◽  
Ankit Gupta ◽  
Monika ◽  
Richa ◽  
Renu Chadha ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Synthesis ◽  
Thymidylate Synthase ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
External Validation ◽  
3D Qsar ◽  
Synthesis Process ◽  
Human Beings ◽  
Thymidylate Synthase Inhibitors

Introduction: Lung cancer is presumed to be the most notable cause of morbidity and impermanency in human beings caused by uncontrolled cell proliferation of lung tissue which results in abrupt synthesis of DNA. Methods: Prevention of DNA synthesis can show distinctive effect on lung cancer by utilizing Thymidylate synthase (TS), a key rate-limiting enzyme in the DNA synthesis process. However, the available finite aggregate of clinically approved blockers and their corresponding side effects lead to the urgent origination of novel inhibitors. Results and Discussion: In silico approaches (QSAR and molecular docking) have been accomplished to discover new potential inhibitors of TS providing a new strategy to evolve novel thymidylate synthase inhibitors functional in lung cancer. Conclusion: In the present study chemical features of a series of compounds alongside their activities alternating over numerous orders of magnitudes was utilized to generate QSAR models, and these could be further employed to predict the activity of new designed compounds. 3D‒QSAR kNNSW based model with decent statistical data having q2 approximately 95% (internal validation) and 80% (external validation) has validated the importance of steric feature. Further docking analysis using D‒score and ligand receptor interactions indicated that all the studied compounds are well accommodated in the binding pocket of TS and disparities in the activity are controlled by hydrogen and hydrophobic interactions.

scholarly journals Virtual Screening and ADMET Studies to Identify KSP Inhibitors as Anticancer Therapeutics

2017 ◽  
Vol 9 (1) ◽  
pp. 1
Author(s):  
Raadhika Chelamalla ◽  
Ajitha Makula
Keyword(s):  
Virtual Screening ◽  
Binding Energies ◽  
Proof Of Concept ◽  
Computational Approaches ◽  
Structural Modifications ◽  
Medical Need ◽  
Pharmacokinetic Properties ◽  
Ksp Inhibitors ◽  
Affinity Receptor ◽  
Potential Inhibitors

<p>Virtual Screening plays an important role to achieve binding affinity, receptor and library pre-processing, docking, scoring and top scoring hits. Optimization of drug ADME parameters continues to play an important role to ensure that the exposure is sufficient to achieve proof of concept, and ultimately efficacy, safely in clinical trials to address unmet medical need.<strong> </strong>In order to identify potential inhibitors we employed various computational approaches. In this work, we computationally screened and analyzed 60 analogs and further tested their ADME/T profiles.<strong> </strong>Library of the molecules was constructed based upon structural modifications of pyrimidines and indole nucleus. Structural modifications were performed for the series of 4-(3-hydroxyphenyl)-6-methyl-2-oxo-N-substituted[(Z)-(2-oxoindolin-3-ylidene)amino]-3,4-dihydro-1H-pyrimidine-5-carboxamide derivatives in an order to get better  binding energies as compared with Ispinseb. The molecules with better (lower) binding energies were subjected to predict ADMET properties. Ten molecules from the series IP1-IP60 were found acceptable with binding energies and pharmacokinetic properties. On the basis of the binding energies and ADMET properties we have identified compound IP2 and IP4 to be the best interacting molecules. The molecules with acceptable ADMET properties and better binding energies were prioritized for synthesis and anticancer evaluation. </p>

Synthesis and In-silico Studies of C-4 Substituted Coumarin Analogues as Anticancer Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Jyoti Dandriyal ◽  
Kamalpreet Kaur ◽  
Vikas Jaitak
Keyword(s):  
Anticancer Agents ◽  
Active Site ◽  
In Silico ◽  
Oral Absorption ◽  
In Vivo Studies ◽  
Conventional Heating ◽  
Microwave Assisted Synthesis ◽  
Standard Drug ◽  
In Silico Studies ◽  
Adme Properties

Background: Coumarin is a fused ring system and possesses enormous capability of targeting various receptors participating in cancer pathway. Coumarin and its derivatives were found to exhibit very rare toxicity and other side effects. It has been found its immense anticancer potential depends on the nature of group present and its pattern of substitution on the basic nucleus. Objectives: Synthesis of C-4 substituted coumarin derivatives and to study their molecular interactions with ERα for anticancer activity for Breast Cancer. Method: C-4 substituted coumarins analogues (1-10) have been synthesized using conventional heating and microwave irradiation. Using Schrodinger software molecular modeling studies were carried out and ADME properties of the compounds were predicted. Results: All the synthesized compounds have shown better G-Score (-6.87 to -8.43 kcal/mol) as compared to the standard drug tamoxifen (-5.28kcal/mol) and auraptene (-3.89kcal/mol). Molecular docking suggests that all compounds fit in the active site of protein as they have the same hydrophobic pocket as standard drug tamoxifen, and have an acceptable range of ADME properties. Conclusion: Microwave-assisted synthesis showed better results as compared to conventional heating. In-silico studies revealed that all the compounds befit in the active site of protein. ADME properties showed that all compounds are in allowable limits for human oral absorption. In future, there is a possibility of in-vitro and in-vivo studies of the synthesized compounds.

scholarly journals Identification of Potential HCV Inhibitors Based on the Interaction of Epigallocatechin-3-Gallate with Viral Envelope Proteins

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1257
Author(s):  
Fareena Shahid ◽  
Noreen ◽  
Roshan Ali ◽  
Syed Lal Badshah ◽  
Syed Babar Jamal ◽  
...  
Keyword(s):  
Hepatitis C ◽  
In Silico ◽  
Experimental Validation ◽  
Homology Modelling ◽  
Viral Envelope ◽  
Screening Methods ◽  
Binding Affinities ◽  
Autodock Vina ◽  
Potential Inhibitors ◽  
Very High

Hepatitis C is affecting millions of people around the globe annually, which leads to death in very high numbers. After many years of research, hepatitis C virus (HCV) remains a serious threat to the human population and needs proper management. The in silico approach in the drug discovery process is an efficient method in identifying inhibitors for various diseases. In our study, the interaction between Epigallocatechin-3-gallate, a component of green tea, and envelope glycoprotein E2 of HCV is evaluated. Epigallocatechin-3-gallate is the most promising polyphenol approved through cell culture analysis that can inhibit the entry of HCV. Therefore, various in silico techniques have been employed to find out other potential inhibitors that can behave as EGCG. Thus, the homology modelling of E2 protein was performed. The potential lead molecules were predicted using ligand-based as well as structure-based virtual screening methods. The compounds obtained were then screened through PyRx. The drugs obtained were ranked based on their binding affinities. Furthermore, the docking of the topmost drugs was performed by AutoDock Vina, while its 2D interactions were plotted in LigPlot+. The lead compound mms02387687 (2-[[5-[(4-ethylphenoxy) methyl]-4-prop-2-enyl-1,2,4-triazol-3-yl] sulfanyl]-N-[3(trifluoromethyl) phenyl] acetamide) was ranked on top, and we believe it can serve as a drug against HCV in the future, owing to experimental validation.

scholarly journals In silico investigation of potential inhibitors to main protease and spike protein of SARS-CoV-2 in propolis

2021 ◽  
pp. 100969
Author(s):  
Azza H. Harisna ◽  
Rizky Nurdiansyah ◽  
Putri H. Syaifie ◽  
Dwi W. Nugroho ◽  
Kurniawan E. Saputro ◽  
...  
Keyword(s):  
In Silico ◽  
Spike Protein ◽  
Main Protease ◽  
Potential Inhibitors
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