Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-Like Anti-RSV Agents

Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV infections is still awaiting a positive breakthrough. Several benzimidazole-containing derivatives have been discovered and evaluated in clinical trials, with only some of them being endowed with a promising pharmacokinetic profile. In this context, we applied a computational study based on a careful analysis of a number of X-ray crystallographic data of the RSV F protein, in the presence of different clinical candidates. A deepen comparison of the related electrostatic features and H-bonding motifs allowed us to pave the way for the following molecular dynamic simulation of JNJ-53718678 and then to perform docking studies of the in-house library of potent benzimidazole-containing anti-RSV agents. The results revealed not only the deep flexibility of the biological target but also the most relevant and recurring key contacts supporting the benzimidazole F protein inhibitor ability. Among them, several hydrophobic interactions and π-π stacking involving F140 and F488 proved to be mandatory, as well as H-bonding to D486. Specific requirements turning in RSV F protein binding ability were also explored thanks to structure-based pharmacophore analysis. Along with this, in silico prediction of absorption, distribution, metabolism, excretion (ADME) properties, and also of possible off-target events was performed. The results highlighted once more that the benzimidazole ring represents a privileged scaffold whose properties deserve to be further investigated for the rational design of novel and orally bioavailable anti-RSV agents.

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A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity

Open Chemistry ◽

10.1515/chem-2021-0032 ◽

2021 ◽

Vol 19 (1) ◽

pp. 347-357

Author(s):

Belgin Sever ◽

Mehlika Dilek Altıntop ◽

Yeliz Demir ◽

Cüneyt Türkeş ◽

Kaan Özbaş ◽

...

Keyword(s):

Aldose Reductase ◽

In Silico ◽

Aromatic Aldehydes ◽

Docking Studies ◽

Mouse Fibroblast ◽

L929 Mouse Fibroblast ◽

Orally Bioavailable ◽

L929 Mouse ◽

Solvent Free Reaction

Abstract In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones (1–8), which were prepared by the solvent-free reaction of 2,4-thiazolidinedione with aromatic aldehydes in the presence of urea, were examined for their in vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a K i value of 0.445 ± 0.013 µM. The IC50 value of compound 3 for L929 mouse fibroblast cells was determined as 8.9 ± 0.66 µM, pointing out its safety as an AR inhibitor. Molecular docking studies suggested that compound 3 exhibited good affinity to the binding site of AR (PDB ID: 4JIR). Based upon in silico absorption, distribution, metabolism, and excretion data, the compound is predicted to have favorable pharmacokinetic features. Taking into account the in silico and in vitro data, compound 3 stands out as a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as nondiabetic diseases.

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New Benzodioxole-based Pyrazoline Derivatives: Synthesis and Anticandidal, In silico ADME, Molecular Docking Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180326152726 ◽

2018 ◽

Vol 16 (1) ◽

pp. 82-92 ◽

Cited By ~ 1

Author(s):

Ahmet Özdemir ◽

Belgin Sever ◽

Mehlika Dilek Altıntop

Keyword(s):

In Silico ◽

Fungal Infections ◽

Computational Study ◽

Docking Studies ◽

In Vivo Studies ◽

Heme Group ◽

In Silico Studies ◽

Nih 3T3

Background: Azoles are commonly used in the treatment and prevention of fungal infections. They suppress fungal growth by acting on the heme group of lanosterol 14α-demethylase enzyme (CYP51), thus blocking the biosynthesis of ergosterol. </P><P> Objectives: Due to the importance of pyrazolines in the field of antifungal drug design, we aimed to design and synthesize new pyrazoline-based anticandidal agents. Methods: New pyrazoline derivatives were synthesized via the reaction of 1-(chloroacetyl)-3-(2- thienyl)-5-(1,3-benzodioxol-5-yl)-2-pyrazoline with aryl thiols. These compounds were evaluated for their in vitro antifungal effects on Candida species. Docking studies were performed to predict the affinity of the most effective anticandidal agents to substrate binding site of CYP51. Furthermore, MTT assay was performed to determine the cytotoxic effects of the compounds on NIH/3T3 mouse embryonic fibroblast cell line. A computational study for the prediction of ADME properties of all compounds was also carried out. Results: Compounds 5, 8, 10 and 12 were found as the most potent anticandidal agents against Candida albicans and Candida glabrata in this series with the same MIC values of ketoconazole and they also exhibited low toxicity against NIH/3T3 cells. Docking results indicated that all these compounds showed good binding affinity into the active site of CYP51. In particular, chloro substituted compounds 8 and 12 bind to CYP51 through direct coordination with the heme group. According to in silico studies, compound 8 only violated one parameter of Lipinski’s rule of five, making it a potential orally bioavailable agent. Conclusion: Compound 8 was defined as a promising candidate for further in vitro and in vivo studies.

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In Silico Docking Studies of Antimalarial Drug Hydroxychloroquine to SARS-CoV Proteins :An Emerging Pandemic Worldwide

10.26434/chemrxiv.12488804.v1 ◽

2020 ◽

Author(s):

Priyanka H. Jokhakar ◽

Rishee Kalaria ◽

Hiren K. Patel

Keyword(s):

Antimalarial Drug ◽

Hydrophobic Interactions ◽

Computational Study ◽

Covalent Bond ◽

Docking Studies ◽

Protein Docking ◽

Viral Attachment ◽

Discovery Studio ◽

In Silico Docking ◽

Covalent Bond Formation

<p>This computational study comprises screening and prediction of interaction of selected antimalarial drug hydroxychloroquine with targeted two proteins of coronavirus. One is SARS enveloped E pantameric ion channel protein and another is SARS-CoV-2 main apoprotein protease. Both are vital for viral attachment and entry to the host cell for infection. After molecular protein docking with different confirmations, stable interacting complex of ligand and macromolecules were obtained. Interacting Lysine, Threonine and Tyrosine of E protein were found for participation of stable interaction with selected drug having docking affinity energy of -6.3kcal/mol. For apoprotein protease stable confirmation was screened out having bonding Threonine residue with same drug of energy -6.0 kcal/mol. Irreversible covalent bond formation and van der Waals interaction favours the selectivity and stability of both targeted proteins towards selected drug. Conventional as well as hydrophobic interactions are found in Ligplot and Discovery studio analysis also indicates stabilized confirmations between ligand and drug. Thus, this study delivers the putative mechanism of the drug interactions to target proteins hence comprising landmark for future investigation for antimalarial hydroxychloroquine as anti COVID 19 drug in this experimental time.</p>

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In Silico Docking Studies of Antimalarial Drug Hydroxychloroquine to SARS-CoV Proteins :An Emerging Pandemic Worldwide

10.26434/chemrxiv.12488804 ◽

2020 ◽

Author(s):

Priyanka H. Jokhakar ◽

Rishee Kalaria ◽

Hiren K. Patel

Keyword(s):

Antimalarial Drug ◽

Hydrophobic Interactions ◽

Computational Study ◽

Covalent Bond ◽

Docking Studies ◽

Protein Docking ◽

Viral Attachment ◽

Discovery Studio ◽

In Silico Docking ◽

Covalent Bond Formation

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The inhibitory Effects of Some Artificial Food Colorings on α-amylase and α-glucosidase: In Vitro and In Silico Studies

Current Enzyme Inhibition ◽

10.2174/1573408017666211018102605 ◽

2021 ◽

Vol 17 ◽

Author(s):

Reguia Mahfoudi ◽

Amar Djeridane ◽

Djilali Tahri ◽

Mohamed Yousfi

Keyword(s):

In Silico ◽

Hydrophobic Interactions ◽

Inhibitory Effect ◽

Docking Studies ◽

Qsar Study ◽

Molegro Virtual Docker ◽

Artificial Food ◽

In Silico Studies ◽

Ic50 Values

Background: Inhibition of α-amylase and α-glucosidase is considered as an important therapeutic target to manage type 2 diabetes mellitus (T2DM), reducing postprandial hyperglycemia (PPHG). Objective: The present work explored the antidiabetic activities of five artificial food colorings by α-amylase and α-glucosidase enzyme inhibition in vitro and in Silico. Methods: In this study, inhibition of α-amylase and α-glucosidase were evaluated. Further, the interaction between enzymes (α-amylase and α-glucosidase) and ligands (food colorings) was followed by QSAR and molecular docking studies. Results: The in vitro results obtained show that the blue patent (SIN131) exhibited more potent inhibition with IC50 values of 0.03± 0.01 mM and 0.014±0.001 mM against α-amylase and α-glucosidase inhibition respectively compared to acarbose. The QSAR study found a strong correlation between IC50 values with four molecular descriptors. This linear regression confirms that a strong polarity (Apol) and a low hydrophobia (ALogP) favor the inhibitory effect of these colorings toward both enzymes. Also, a negative role of the number of heavy atoms has been demonstrated in the phenomenon of inhibition of this enzyme. Finally, the descriptor εlumo (electronic affinity) plays a crucial role on the inhibitory power of these dyes toward both enzymes by electron transfer. The virtual screening of the inhibition of α-amylase and α-glucosidase by these colorings, using Molegro Virtual Docker (MVD), allowed us to obtain stable complexes with interaction energies resulting from the place of hydrogen bonds and several hydrophobic interactions. However, the sulfonate groups of these colorings can be the major factors in the inhibition of these enzymes. On the other hand, Rerank Score with the pose are perfectly correlated (R2> 0.76) to the inhibitory activity of these food colorings measured experimentally. Conclusion: The present study suggests that the Blue Patent V (SIN131) effectively act as α-amylase and α-glucosidase inhibitor leading to a reduction in starch hydrolysis and hence eventually to lowered glucose levels.

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In silico discovery of novel phytoconstituents of Amyris pinnata as mitotic spindle kinase inhibitor

Current Drug Research Reviews ◽

10.2174/2589977512666200220122211 ◽

2020 ◽

Vol 12 ◽

Author(s):

Ghanshyam R. Parmar ◽

Ashish P. Shah ◽

Girish U. Sailor ◽

Avinash Kumar Seth

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

Mitotic Spindle ◽

In Silico ◽

Kinase Inhibitor ◽

Pharmacokinetic Profile ◽

Docking Studies ◽

Chemotherapeutic Agents ◽

Cancer Disease ◽

Molecular Docking Studies

Background: Despite of many successes in discovery of numerous cancer chemotherapeutic agents from natural sources, some of the moieties were dropped because of its inefficiency or serious toxicity. Mitosis is an ordered series of fundamentally mechanical events in which identical copies of the genome are moved to two discrete locations within the dividing cell. The crucial role of the mitotic spindle in cell division has identified which is an important target in cancer chemotherapy. In the present study we are reporting molecular docking studies and in silico pharmacokinetic profile of selected phytoconstituents obtained from Amyris pinnata. Methods: Molecular docking studies of selected phytoconstituents were performed using iGEMDOCK. The crystal structure of protein was exported from protein data bank (PDB id: 4C4H). In silico pharmacokinetic profile of selected phytoconstituents were performed using SWISSADME server. Results: Compound AMNP6 showed higher binding affinity as compared to standard ligand. All the selected phytoconstituents has passed Lipinski rule of five and shown no violations. Conclusion: Good binding affinity and drug likeliness of the AMNP6 suggest that it can be further investigated and explored as mitotic spindle kinase inhibitor in cancer disease.

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In vitro and in silico studies on AChE inhibitory effects of a series of donepezil-like arylidene indanones

Turkish Journal of Biochemistry ◽

10.1515/tjb-2019-0356 ◽

2020 ◽

Vol 45 (4) ◽

pp. 359-363

Author(s):

Belgin Sever ◽

Mehlika Dilek Altıntop ◽

Halide Edip Temel

Keyword(s):

Molecular Docking ◽

In Silico ◽

Binding Mode ◽

Docking Studies ◽

Ache Inhibitor ◽

Ache Inhibition ◽

Lipinski’S Rule ◽

In Silico Studies ◽

Orally Bioavailable

AbstractObjectiveDonepezil is the most potent acetylcholinesterase (AChE) inhibitor currently available on the market for the management of Alzheimer’s disease. In this study, it was aimed to identify potent donepezil analogues.Materials and methodsThe effects of arylidene indanones (1–10) on AChE inhibition were examined using modified Ellman’s assay. Compound 4, the most potent arylidene indanone in this series, was subjected to molecular docking to anticipate its binding mode in the AChE site (PDB code: 4EY7). The pharmacokinetic profiles of all derivatives were also predicted.ResultsCompound 4 was found as the most potent AChE inhibitor with an IC50 value of 5.93 ± 0.29 μg/mL. According to molecular docking studies, compound 4 presented favorable interactions such as π–π interactions with Trp286 and Tyr337. In silico studies revealed that the compound did not violate Lipinski’s rule of five and Jorgensen’s rule of three, making it a potential orally bioavailable agent.ConclusionCompound 4 is a feasible candidate for further experiments related to AChE inhibition.

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Synthesis of Coumarins Linked With 1,2,3-Triazoles under Microwave Irradiation and Evaluation of their Antimicrobial and Antioxidant Activity

Journal of the Mexican Chemical Society ◽

10.29356/jmcs.v64i1.1116 ◽

2019 ◽

Vol 64 (1) ◽

Author(s):

Nibin Joy Muthipeedika ◽

Yadav D Bodke ◽

Sandeep Telkar ◽

Vasily A Bakulev

Keyword(s):

Antioxidant Activity ◽

In Silico ◽

Hydrophobic Interactions ◽

Antioxidant Properties ◽

Cycloaddition Reaction ◽

Antibacterial Activities ◽

Docking Studies ◽

In Silico Docking ◽

Antimicrobial And Antioxidant Activity ◽

Plausible Reason

A series of coumarin derivatives linked with 1,2,3-triazoles has been synthesized by utilizing the copper catalyzed azide-alkyne cycloaddition reaction and were screened for their antimicrobial and antioxidant properties. Some of the compounds displayed promising antibacterial activities (MIC ranging from 5-150 µg/mL) and moderate antifungal activities as compared to the respective standards. The compounds 4k and 4g displayed good antibacterial activity when compared with the standard, Ciprofloxacin, and 4n exhibited better antifungal activity when compared to other synthesized compounds. The in silico docking studies of the active compounds were carried out against the gyrase enzyme and from those studies, it was acknowledged that 4k possessed significant hydrogen bonding and hydrophobic interactions which could be the plausible reason for its superior activity as compared to the other synthesized compounds. The compounds 4h and 4q showed promising antioxidant activity when compared with the standard, BHT, which could be attributed to the presence of electron donating substituents. Resumen. Una serie de derivados de cumarina enlazados con 1,2,3-triazoles fue sintetizada empleando la reacción de cicloadición azida-alquino catalizada con cobre y fue evaluada en sus propiedades antimicrobianas y antioxidantes. Algunos de los compuestos exhibieron actividad antimicrobiana promisoria (intervalo MIC de 5-150 µg/mL) y actividad antifúngica moderada con respecto a los estándares respectivos. Los compuestos 4g y 4k mostraron buena actividad antibacterial con relación al estándar. Fluconazole y 4n exhibieron mejor actividad antifúngica en comparación con el resto de los compuestos. Se llevaron a cabo estudios in silico de modelado molecular e interacción de los compuestos activos con la enzima girasa ADN. De estos estudios se observó que 4k posee enlaces puentes de hidrógeno e interacciones hidrofóbicas significativos, los cuales podrían ser una causa plausible de su actividad mayor a aquélla mostrada por los otros compuestos sintetizados. Los compuestos 4h y 4q mostraron una importante actividad antioxidante comparada con el estándar (BHT), lo cual podría atribuirse a la presencia de sustituyentes electro-donadores

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2-Butyl-6-phenyl-4,5-dihydropyridazin-3(2H)-one: Synthesis, In Silico Studies and In Vitro Cyclooxygenase-2 Inhibitory Activity

Molbank ◽

10.3390/m1155 ◽

2020 ◽

Vol 2020 (3) ◽

pp. M1155

Author(s):

Mohd Imran

Keyword(s):

In Silico ◽

Pharmacokinetic Profile ◽

Docking Studies ◽

Cyclooxygenase 2 ◽

Pharmacokinetic Parameters ◽

Butyl Bromide ◽

In Silico Studies ◽

Cox 2 ◽

Pyridazinone Derivatives

Pyridazinone derivatives are a great template for developing cyclooxygenase-2 (COX-2) inhibitors. The 2-butyl-6-phenyl-4,5-dihydropyridazin-3(2H)-one was prepared by reacting 6-phenyl-4,5-dihydropyridazin-3(2H)-one with n-butyl bromide in the presence of potassium carbonate. The structure of the compound was confirmed based on its FTIR, 1H-NMR, 13C-NMR, and Mass data. The molecular docking studies assessed the COX-2 binding capability of the synthesized compound. The in silico physicochemical and pharmacokinetic parameters of this compound concerning selected drugs were also calculated. The COX-2/COX-1 analysis revealed the synthesized compound as a novel potent COX-2 inhibitor, in comparison to indomethacin, with a promising physicochemical and pharmacokinetic profile.

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IN SILICO DESIGN OF BENOXAZOLE BEARING AZETIDINONE DERIVATIVES AS VEGFR-2 AGONIST IN CANCER

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2021.v14i11.42706 ◽

2021 ◽

pp. 112-115

Author(s):

LEYANA PN ◽

MANJU PT ◽

MEENU VIJAYAN

Keyword(s):

In Silico ◽

Chemical Properties ◽

Binding Pocket ◽

Docking Studies ◽

Vascular Endothelial ◽

In Silico Design ◽

Lipinski’S Rule ◽

Orally Bioavailable ◽

Endothelial Growth Factor ◽

Physical And Chemical

Objective: Cancer is a group of disease characterized by uncontrolled growth of cells. The objective of the study includes the in silico designing of benzoxazole bearing azetidinone derivatives as Vascular Endothelial Growth Factor 2 in cancer. Methods: In silico design of proposed derivatives was conducted using tools such as AutoDock Vina, ACD Lab ChemSketch ver. 12.0, Prediction of Activity Spectra for Substances online, molinspiration, and Swiss ADME. The derivatives obeying Lipinski’s Rule of Five in accordance with molinspiration were selected for docking studies. Results: The data obtained from molinspiration revealed that the designed derivatives have physical and chemical properties meant for an orally bioavailable drug. From the docking studies derivatives BT1 and BT5 showed high docking score which indicate that these derivatives possess high affinity and high polar interaction towards protein 4DBN. Conclusion: The designed benzoxazole bearing azetidinone derivatives were found to possess good binding affinity and good interaction in the binding pocket of the target 4DBN. Therefore, these derivatives are expected to exhibit good anticancer property with minimal side effects.

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