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 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.

scholarly journals 2-Oxoquinoline Arylaminothiazole Derivatives in Identifying Novel Potential Anticancer Agents by Applying 3D-QSAR, Docking, and Molecular Dynamics Simulation Studies

2021 ◽  
Vol 66 (1) ◽  
Author(s):  
Reda El-Mernissi ◽  
Khalil El Khatabi ◽  
Ayoub Khaldan ◽  
Larbi ElMchichi ◽  
Md Shahinozzaman ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Anticancer Agents ◽  
Hydrophobic Interactions ◽  
External Validation ◽  
Cancer Cell Line ◽  
3D Qsar ◽  
Dynamics Simulation ◽  
Cytotoxicity Activity ◽  
Tubulin Inhibitors

Abstract. Tubulin plays an indispensable role in regulating various important cellular processes. Recently, it is known as a hopeful therapeutic target for the rapid division of cancer cells. Novel series of 2-oxoquinoline arylaminothiazole derivatives have been recently identified as promising tubulin inhibitors with potent cytotoxicity activity against HeLa cancer cell line. In this study, a 3D-QSAR approach by using CoMFA and CoMSIA techniques was applied to the reported derivatives to understand their pharmacological essentiality contributing to the tubulin inhibition activity and selectivity. The optimum CoMFA and CoMSIA models were found to have significant statistical reliability and high predictive ability after internal and external validation. By analyzing the contour maps, the electrostatic and hydrophobic interactions were found to be crucial for improving the inhibitory activity and four novel tubulin inhibitors (Compounds D1, D2, D3, and D4) were designed based on the validated 3D-QSAR models. Moreover, the docking findings showed that residues Gln136, Val238, Thr239, Asn167, Val 318 and Ala 316 played important roles for quinoline binding to tubulin. Among the newly designed compounds, compound D1 with the highest total scoring was subjected to detailed molecular dynamics (MD) simulation and compared to the most active compound. The conformational stability of compound D1 complexed with tubulin protein was confirmed by a 50-ns molecular dynamics simulation, which was congruent with molecular docking.   Resumen. La tubulina juega un papel indispensable en la regulación de varios procesos celulares importantes. Recientemente, se le ha reconicodo como un agente promisorio para atacar la rápida división de las células cancerosas. Últimamente se ha identificado una nueva serie de derivados de arilaminotiazo-2-oxoquinolina como potenciales inhibidores de la tubulina, con una elevada actividad citotóxica contra la línea celular de cáncer HeLa. En este estudio, se aplicó a los derivados informados un estudio 3D-QSAR mediante el uso de técnicas CoMFA y CoMSIA para comprender los factores farmacológicos que contribuyen a la actividad como inhibidor y selectivo de la tubulina. Se encontró que los modelos CoMFA y CoMSIA óptimos tienen una confiabilidad estadística significativa y una alta capacidad predictiva después de la validación interna y externa. Al analizar los mapas de contorno, se descubrió que las interacciones electrostáticas e hidrófobas eran cruciales para mejorar la actividad inhibidora y se diseñaron cuatro nuevos inhibidores de la tubulina (compuestos D1, D2, D3 y D4) basados en los modelos 3D-QSAR validados. Además, los hallazgos de acoplamiento mostraron que los residuos Gln136, Val238, Thr239, Asn167, Val 318 y Ala 316 desempeñaron papeles importantes en la unión de la quinolina a la tubulina. Entre los compuestos de nuevo diseño, el compuesto D1 con la puntuación total más alta se sometió a una simulación detallada de dinámica molecular (MD) y se comparó con el compuesto más activo. La estabilidad conformacional del compuesto D1 unido a la proteína tubulina se confirmó mediante una simulación de dinámica molecular de 50 ns, que fue congruente con el acoplamiento molecular.

In Silico Anticancer Evaluation, Molecular Docking and Pharmacophore Modeling of Flavonoids against Various Cancer Targets

2020 ◽  
Vol 17 (12) ◽  
pp. 1485-1501
Author(s):  
Jainey Puthenveettil James ◽  
Pankaj Kumar ◽  
Abhishek Kumar ◽  
Katte Ishwar Bhat ◽  
Chakrakodi Shashidhara Shastry
Keyword(s):  
Colorectal Cancer ◽  
Lung Cancer ◽  
Molecular Docking ◽  
Anticancer Agents ◽  
In Silico ◽  
Active Sites ◽  
Hydrophobic Interactions ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Score

Background: Designing and development of molecules for cancer treatment useful and with no side effects are a big challenge for the researchers in the field of drug discovery. The use of phytochemicals for chemoprevention is gaining more advantages, and intake of flavonoids has proved to reduce the occurrence of various cancers. Objectives: The present study was focused on selecting eight flavonoids and study them by in silico methods to analyse the interactions, affinity and pharmacophoric features that participate in the interactions between the flavonoid and the active sites of different cancer targets. Methods: The cancer targets were downloaded from the protein data bank, and flavonoids from PubChem and were docked by Glide XP molecular docking method to find the molecular interactions. The binding energy was calculated by Prime MM-GBSA application and ADMET analysis by Qikprop of Schrodinger. The anticancer potential of flavonoids screening was based on an online tool, Pass predictor. Phase module was used to find the common pharmacophore features that participate in essential interactions between the flavonoid and the active site. Results: In this study, myricetin has proved to be the best flavonoid for the treatment of breast and lung cancer with docking score of -11.50 kcal/mol and -10.56 kcal/mol respectively, whereas, quercetin has proved to be the best for prostate and colorectal cancer with docking score of -14.18 kcal/mol and -12.94 kcal/mol, respectively. The responsible forces for the interaction of these flavonoids are hydrogen bond, hydrophobic interactions, polar and pi-pi stackings. The PASS tool predicted the anticancer potential for the flavonoids, in particular, myricetin had responded highly active for most cancer cells. The hypothesis AADRR_1 has the highest survival score, which indicates the best alignment of the active ligands and represents the best pharmacophore model for anticancer activity. Conclusion: This work has screened eight flavonoids against various cancer targets and shown the binding interactions between them, stating that myricetin is the suitable lead candidate for breast and lung cancer; whereas, quercetin is the best lead for prostate and colorectal cancer. And these data are about the results obtained from PASS predictor. Moreover, the pharmacophore model has generated for the flavonoids, which correlate activities with the spatial arrangement of various chemical features. Therefore, this investigation strongly suggests that these flavonoids can be used as leads as anticancer agents.

Role of 4-O Galloylchlorogenic Acid in Lung Cancer- An Insilico Approach

2017 ◽  
Vol 9 (5) ◽  
Author(s):  
Jaynthy C. ◽  
N. Premjanu ◽  
Abhinav Srivastava
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
In Silico ◽  
Computational Study ◽  
Regulation Mechanism ◽  
Down Regulation ◽  
Fruit Extract ◽  
In Vitro Techniques ◽  
Discovery Studio

Cancer is a major disease with millions of patients diagnosed each year with high mortality around the world. Various studies are still going on to study the further mechanisms and pathways of the cancer cell proliferation. Fucosylation is one of the most important oligosaccharide modifications involved in cancer and inflammation. In cancer development increased core fucosylation by FUT8 play an important role in cell proliferation. Down regulation of FUT8 expression may help cure lung cancer. Therefore the computational study based on the down regulation mechanism of FUT8 was mechanised. Sapota fruit extract, containing 4-Ogalloylchlorogenic acid was used as the inhibitor against FUT-8 as target and docking was performed using in-silico tool, Accelrys Discovery Studio. There were several conformations of the docked result, and conformation 1 showed 80% dock score between the ligand and the target. Further the amino acids of the inhibitor involved in docking were studied using another tool, Ligplot. Thus, in-silico analysis based on drug designing parameters shows that the fruit extract can be studied further using in-vitro techniques to know its pharmacokinetics.

3D-QSAR, molecular docking and in silico ADMET studies of propiophenone derivatives with anti-HIV-1 protease activity

2021 ◽  
Author(s):  
Milan Jovanović ◽  
Nemanja Turković ◽  
Branka Ivković ◽  
Zorica Vujić ◽  
Katarina Nikolić ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Protease Activity ◽  
3D Qsar ◽  
In Silico Admet ◽  
Anti Hiv ◽  
Hiv 1

1,25(OH) 2 D 3 attenuates sleep disturbance in mouse models of Lewis lung cancer, in silico and in vivo

2021 ◽  
Author(s):  
Min Ai ◽  
Shuang‐shuang Li ◽  
Hong Chen ◽  
Xi‐ting Wang ◽  
Jiang‐nan Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Sleep Disturbance ◽  
Mouse Models ◽  
In Silico ◽  
Lewis Lung ◽  
Lewis Lung Cancer

Efficacy of Pemetrexed in Relapsed Non-Small Cell Lung Cancer and Thymidylate Synthase Expression

2009 ◽  
Vol 67 (3) ◽  
pp. 191 ◽  
Author(s):  
Choel-Kyu Park ◽  
Kyu-Sik Kim ◽  
In-Jae Oh ◽  
Manaljav Tseden-Ish ◽  
Yoo-Duk Choi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Thymidylate Synthase ◽  
Small Cell ◽  
Small Cell Lung
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