scholarly journals Molecular Docking and Binding Mode Analysis of Plant Alkaloids as in Vitro and in silico Inhibitors of Trypanothione Reductase from Trypanosoma cruzi

2016 ◽  
Vol 11 (1) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Alonso J. Argüelles ◽  
Geoffrey A. Cordell ◽  
Helena Maruenda
Keyword(s):  
Molecular Docking ◽  
Trypanosoma Cruzi ◽  
Structural Diversity ◽  
Binding Mode ◽  
Mode Analysis ◽  
Trypanothione Reductase ◽  
Binding Interactions ◽  
Preferential Binding ◽  
Key Enzyme

Trypanothione reductase (TryR) is a key enzyme in the metabolism of Trypanosoma cruzi, the parasite responsible for Chagas disease. The available repertoire of TryR inhibitors relies heavily on synthetic substrates of limited structural diversity, and less on plant-derived natural products. In this study, a molecular docking procedure using a Lamarckian Genetic Algorithm was implemented to examine the protein-ligand binding interactions of strong in vitro inhibitors for which no X-ray data is available. In addition, a small, skeletally diverse, set of natural alkaloids was assessed computationally against T. cruzi TryR in search of new scaffolds for lead development. The preferential binding mode (low number of clusters, high cluster population), together with the deduced binding interactions were used to discriminate among the virtual inhibitors. This study confirms the prior in vitro data and proposes quebrachamine, cephalotaxine, cryptolepine, (22 S,25 S)-tomatidine, (22 R,25 S)-solanidine, and (22 R,25 R)-solasodine as new alkaloid scaffold leads in the search for more potent and selective TryR inhibitors.

scholarly journals Identification of novel thiadiazin derivatives as potentially selective inhibitors towards trypanothione reductase from Trypanosoma cruzi by molecular docking using the numerical index poses ratio Pr and the binding mode analysis

2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Julieta Coro-Bermello ◽  
Ernesto R. López-Rodríguez ◽  
Javier E. Alfonso-Ramos ◽  
Dayana Alonso ◽  
Gerardo M. Ojeda-Carralero ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Trypanosoma Cruzi ◽  
Ad Hoc ◽  
Binding Mode ◽  
Mode Analysis ◽  
Trypanothione Reductase ◽  
Binding Modes ◽  
Hybrid Ligands ◽  
Hydrophobic Cleft ◽  
Numerical Index

Abstract Chagas disease is a serious health problem in Central and South America for which effective treatment is not currently available. This illness is caused by the protozoa Trypanosoma cruzi, a species that relies on a thiol-based metabolism to regulate oxidative stress. Trypanothione reductase enzyme plays a central role in the metabolic pathway of the parasite. In this work, a virtual screening of a library of novel thiadiazine derivatives against trypanothione reductase using molecular docking was performed. Four different series of hybrid ligands having in the structure one or two peptoid moieties (series I and II) or the tetrazole ring (series III and IV) were considered. An ad hoc numerical index called poses ratio was introduced to interpret the results of the docking analysis and to establish relevant structure-interaction relationships. In addition, six binding modes were found for the ligands with the highest populated conformational clusters after applying contact-based analysis. The most regular and relevant were binding modes I and II, found mainly for ligands from series I. A subsequent molecular docking on human glutathione reductase enzyme allowed to assess the possible cytotoxicity of the ligands towards human cells. A selective binding profile was found for ligands with interactions in the Hydrophobic cleft, the spermidine and the Z subsites inside the active site of trypanothione reductase. At the end of the study, new thiadiazine-based compounds were identified as plausible candidates to selectively inhibit the parasitic enzyme. Graphic abstract

Design, Synthesis, Molecular Docking and Biological Studies of New Heterocyclic Compounds Derived from -Diketonesas Novel EGFR and Pim-1 Inhibitors Endowed with Antitumor Activity

2022 ◽  
Vol 22 ◽  
Author(s):  
Rafat Milad Mohareb ◽  
Noha M. Asaad Bagato ◽  
Ibrahim Taha Radwan
Keyword(s):  
Molecular Docking ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Diethyl Malonate ◽  
Binding Mode ◽  
Binding Modes ◽  
Binding Interactions ◽  
Biological Studies

Background: Cancer is a disease illustrated by a shift in the controlled mechanisms that control both cell proliferation and differentiation. It is regarded as a prime health problem worldwide, leading cause of human death-rate exceeded only by cardiovascular diseases. Many reported work was concerned with the discovery of new antitumor compounds this encourage us to synthesis new anticancer agents. Objective: In this work, we are aiming to synthesize target molecules from 1,3-dicarbonyl compounds through many heterocyclization reactions. Method: The reaction of either 4-methylaniline (1a) or 1-naphthylamine (1b) with diethyl malonate (2) gave the anilide derivatives 3a and 3b, respectively. The latter products underwent a series of heterocyclization reactions to give the pyridine, pyran andthiazole derivatives which confirmed with the required spectral data. Results: Thein-vitro antitumor evaluations of the newly synthesized products against four cancer cell lines MCF-7, NCI-H460, SF-268 and WI 38 as normal cell line were screened and the data revealed that compounds 11a, 18b, 18c and 20d showed high antitumor activity and 20dindividualize with potential antitumor activity towards cell lines with lowest cytotoxicity effect. Both EGFR and PIM-1 enzyme inhibition were investigated for the compound 20d and his inhibition effect was promising for each enzyme showing IC50=45.67 ng and 553.3 ng for EGFR and PIM-1, respectively. Conclusion: Molecular docking results of compound 20d showed a strong binding interactions on both enzymes, where, good binding modes obtained on case of EGFR, which closely similar to the binding mode of standard Erlotinib. While, 20d showed complete superimposition binding interactions with VRV-cocrystallized ligand of PIM-1 that may expounds the in-vitro antitumor activity.

In Vitro, Molecular Docking, and In Silico Binding Mode Analysis of Organic Compounds for Antimicrobial and Anticancer Activity against Jurkat, HCT116, and A549 Cell Lines.

2020 ◽  
Vol 5 (41) ◽  
pp. 12807-12818
Author(s):  
Sanay Naha ◽  
Shivaraja Govindaiah ◽  
Swamy Sreenivasa ◽  
Jeevan Kallur Prakash ◽  
Sivan Velmathi
Keyword(s):  
Molecular Docking ◽  
Anticancer Activity ◽  
Organic Compounds ◽  
Cell Lines ◽  
A549 Cell ◽  
In Silico ◽  
Binding Mode ◽  
Mode Analysis

Design, Synthesis, Molecular Docking and Biological Evaluation of 1-(benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol Derivatives as Antiproliferative Agents

2019 ◽  
Vol 16 (10) ◽  
pp. 837-845
Author(s):  
Sandhya Jonnala ◽  
Bhaskar Nameta ◽  
Murthy Chavali ◽  
Rajashaker Bantu ◽  
Pallavi Choudante ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Activity ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Mouse Skin ◽  
Coupling Reaction ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Design Synthesis

A class of 1-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)naphthalen-2-ol derivatives (4a-t) has been synthesized in good yields through a three component coupling reaction. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against five cell lines such as DU145 (human prostate cancer), MDA-MB-B231 (human breast cancer), SKOV3 (human ovarian cancer), B16-F10 (mouse skin melanoma) and CHO-K1 (Chinese hamster ovary cells), a noncancerous cell line. In vitro inhibitory activity indicates that compounds 4a, 4b, 4c, 4d, 4g, 4j, and 4o exhibited potent anti-proliferative behavior. Among them, compounds 4g, 4j and 4o found to be the most active members exhibiting remarkable growth inhibitory activity. Molecular docking facilitates to investigate the probable binding mode and key active site interactions in tubulins α and β proteins. The docking results are complementary to experimental results.

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

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.

scholarly journals Biological Evaluation, Molecular Docking, and SAR Studies of Novel 2-(2,4-Dihydroxyphenyl)-1H- Benzimidazole Analogues

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 870
Author(s):  
Joanna Matysiak ◽  
Alicja Skrzypek ◽  
Monika Karpińska ◽  
Kamila Czarnecka ◽  
Paweł Szymański ◽  
...  
Keyword(s):  
Molecular Docking ◽  
High Selectivity ◽  
Antioxidant Properties ◽  
Binding Mode ◽  
Biological Evaluation ◽  
The Other ◽  
Docking Simulations ◽  
Sar Studies ◽  
Structure Activity

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman’s spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC50 80–90 nM) AChE and moderate (IC50 5–0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure–activity relationships were discussed. The compounds inhibited also in vitro self-induced Aβ(1–42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.

scholarly journals Crude extract and isolated bioactive compounds from Notholirion thomsonianum (Royale) Stapf as multitargets antidiabetic agents: in-vitro and molecular docking approaches

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mater H. Mahnashi ◽  
Yahya S. Alqahtani ◽  
Ali O. Alqarni ◽  
Bandar A. Alyami ◽  
Muhammad Saeed Jan ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Molecular Docking ◽  
Research Work ◽  
Docking Studies ◽  
Common Disease ◽  
World Population ◽  
Binding Interactions ◽  
Molecular Docking Studies ◽  
Crude Extracts

Abstract Background Diabetes mellitus is a common disease effecting the lifestyles of majority world population. In this research work, we have embarked the potential role of crude extracts and isolated compounds of Notholirion thomsonianum for the management diabetes mellitus. Methods The crude extracts of N. thomsonianum were initially evaluated for α-glucosidase, α-amylase and antioxidant activities. The compounds were isolated from the activity based potent solvent fraction. The structures of isolated compounds were confirmed with NMR and MS analyses. The isolated compounds were tested for α-glucosidase, α-amylase, protein tyrosine phosphatase 1B (PTP1B) and DPPH activities. The molecular docking studies were carried out to find the binding interactions of isolated compounds for α-glucosidase, α-amylase and PTP1B. Results Initially, we screened out crude extracts and subfractions of N. thomsonianum against different in-vitro targets. Among all, Nt.EtAc was observed a potent fraction among all giving IC50 values of 67, 70, < 0.1, 89 and 16 μg/mL against α-glucosidase, α-amylase, DPPH, ABTS and H2O2 respectively. Three compounds (Nt01, Nt02 and Nt03) were isolated from Nt.EtAc of N. thomsonianum. The isolated compounds Nt01, Nt02 and Nt03 exhibited IC50 values of 58.93, 114.93 and 19.54 μM against α-glucosidase, while 56.25, 96.54 and 24.39 μM against α-amylase respectively. Comparatively, the standard acarbose observed IC50 values were 10.60 and 12.71 μM against α-glucosidase, α-amylase respectively. In PTP1B assay, the compounds Nt01, Nt02 and Nt03 demonstrated IC50 values of 12.96, 36.22 and 3.57 μM in comparison to the standard ursolic acid (IC50 of 3.63 μM). The isolated compounds also gave overwhelming results in DPPH assay. Molecular docking based binding interactions for α-glucosidase, α-amylase and PTP1B were also encouraging. Conclusions In the light of current results, it is obvious that N. thomsonianum is potential medicinal plant for the treatment of hyperglycemia. Overall, Nt.EtAc was dominant fraction in all in-vitro activities. Three compounds Nt01, Nt02 and Nt03 were isolated from ethyl acetate fraction. The Nt03 specifically was most potent in all in-vitro assays. The molecular docking studies supported our in-vitro results. It is concluded that N. thomsonianum is a rich source of bioactive antidiabetic compounds which can be further extended to in-vivo based experiments.

scholarly journals Structural Insights into Novel 15-Prostaglandin Dehydrogenase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5903
Author(s):  
Prema L. Mallipeddi ◽  
Yongyou Zhang ◽  
Hongyun Li ◽  
Sanford D. Markowitz ◽  
Bruce Posner
Keyword(s):  
Binding Mode ◽  
Marrow Transplant ◽  
Docking Studies ◽  
Binding Interactions ◽  
Prostaglandin Dehydrogenase ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Structural Insights

We discovered SW033291 in a high throughput chemical screen aimed at identifying 15-prostaglandin dehydrogenase (15-PGDH) modulators. The compound exhibited inhibitory activity in in vitro biochemical and cell-based assays of 15-PGDH activity. We subsequently demonstrated that this compound, and several analogs thereof, are effective in in vivo mouse models of bone marrow transplant, colitis, and liver regeneration, where increased levels of PGE2 positively potentiate tissue regeneration. To better understand the binding of SW033291, we carried out docking studies for both the substrate, PGE2, and an inhibitor, SW033291, to 15-PGDH. Our models suggest similarities in the ways that PGE2 and SW033291 interact with key residues in the 15-PGDH-NAD+ complex. We carried out molecular dynamics simulations (MD) of SW033291 bound to this complex, in order to understand the dynamics of the binding interactions for this compound. The butyl side chain (including the sulfoxide) of SW033291 participates in crucial binding interactions that are similar to those observed for the C15-OH and the C16-C20 alkyl chain of PGE2. In addition, interactions with residues Ser138, Tyr151, and Gln148 play key roles in orienting and stabilizing SW033291 in the binding site and lead to enantioselectivity for the R-enantiomer. Finally, we compare the binding mode of (R)-S(O)-SW033291 with the binding interactions of published 15-PGDH inhibitors.

scholarly journals SYNTHESIS AND ANTICANCER SCREENING OF TRIAZINE ANALOGUES

2019 ◽  
pp. 114-121
Author(s):  
Anshuly Tiwari ◽  
Siddharth J. Modi ◽  
KAKASAHEB R MAHADIK ◽  
Mugdha R. Suryawanshi
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Molecular Docking ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Binding Mode ◽  
Spectroscopic Techniques ◽  
Epidermal Growth

Objective: The study was aimed to investigate the cytotoxic effect of S-5H-[1,2,4]-triazino (5,6-b) indol-3-yl-3,4-phenylethane-thioate derivatives as epidermal growth factor Receptor (EGFR) inhibitors. Methods: In the present study 14 novel triazine analogues were synthesized and characterized using different spectroscopic techniques such as FT-IR, NMR and Mass Spectroscopy. The anticancer activity was performed using MCF-7 (breast cancer) and K-562 (leukaemia) cell lines. Further, molecular docking was carried out using Vlife Molecular Docking Software (MDS) on crystal structure of epidermal growth factor receptor (EGFR) to identify the binding mode of interaction with an active site. Results: Compounds MA-7, MA-8, MA-12, MA-13 and MA-14 show potent activity against cancer cell lines in the range of<10 to 84.4 µg/ml. Further molecular docking on EGFR also supports that there is a strong correlation between in silico and in vitro biological activity. The results of this study may be further useful for lead optimization process. Conclusion: The results of this study indicates that the synthesized triazine analogues can give a potential lead as an anticancer agent.

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