De novo Design and in-silico Studies of Coumarin Derivatives as Inhibitors of Cyclin Dependent Kinase-2

In the present study, around sixty-two novel coumarin derivatives were designed as CDK-2 inhibitors based on essential pharmacophoric requirements. All the designed compounds were subjected to docking study using AutoDock 4.2 against CDK-2 protein (PDB ID: 1HCK). Molinspiration and Osiris property explorer were used to predict Lipinski’s rule of five and toxicity profile. The Structure Activity Relationship study revealed that, the substitution at R1 and R4 of coumarin nucleus enhances the binding energy and inhibitory constant values from nanomolar to picomolar range. Among the designed analogues, compound 15, 28, 43 and 59 showed significant binding energy and inhibitory constant values as compared to the standard drug Olomoucine and Deschloroflavopiridol. Most of the designed analogues showed similar binding mode and orientation inside the active site of the protein as that of the standard drug, which strongly indicates that the designed molecules may emerge as potent inhibitors of CDK-2. Next, molecular dynamics study of the significantly active molecule 15 was studied for 10 ns, in order to determine the stability of the coumarin molecules inside the binding cavity of the protein. In-silico investigations suggest that the de novo designed coumarin derivatives were potentially in-silico bioactive and need to be synthesized and tested further.

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Phenolic compounds as antiviral agents: An In-Silico investigation against essential proteins of SARS-CoV-2

10.53365/nrfhh/143085 ◽

2021 ◽

Author(s):

Hammami Majdi ◽

Feten Zar Kalai ◽

Walid Yeddess ◽

Moufida Saidani

Keyword(s):

Phenolic Compounds ◽

Binding Energy ◽

In Silico ◽

Antiviral Agents ◽

Antiviral Drug ◽

Binding Mode ◽

Flavonoid Glycoside ◽

Virus Protein ◽

Therapeutic Effects ◽

Lipinski’S Rule

Plant biodiversity is endowed with a huge composition and variability of active molecules known for their therapeutic effects against several diseases. In this current work, several phenolic compounds are subject of in silico evaluation of their interactions with six severe acute respiratory syndrome coronavirus (SARS-CoV) enzymes to evaluate the binding mode and mechanism of phenolic compounds interactions with SARS-CoV-2 enzymes. Results of molecular docking and data analysis revealed that the importance of interactions was dependent to the phenolic class of tested ligand; tannin, biflavone and flavonoid glycoside were the most interactive classes. Among the top three ranked molecules recording lower binding energy against each virus protein target, In conclusion, it was found that Amentoflavone, Dieckol, Bilobetin, Punicalagin, Tellimagrandin-I, Tannic acid, Sciadopitysin, Ginkgetin and Chebulagic acid could be a promising antiviral drug since they present more important binding energy than conventional ones. Their interactions were justified by the Wenn diagram and Ramachandran plot. However, these phenolic compounds recorded an important bioavailability score and found fulfilling most of the drug-likeness criteria such as Lipinski's rule. Clearly, all observations point to further required works aiming to examine more deeply the possibility of using these molecules that could be probably a subject of pre-clinical studies.

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1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors.

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666201216095018 ◽

2020 ◽

Vol 21 ◽

Author(s):

Elizabeth Eldhose ◽

Kaviarasan Lakshmanan ◽

Praveen T. Krishnamurthy ◽

Kalirajan Rajagopal ◽

Manal Mohammed ◽

...

Keyword(s):

Anticancer Activity ◽

In Silico ◽

Biological Activities ◽

Docking Study ◽

Binding Mode ◽

Oral Toxicity ◽

Standard Drug ◽

In Silico Docking

Background: 1,3,4-thiadiazolo pyrimidine is a lead molécule which is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity. Objective: The objective of the study was to synthesize series of 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] - [1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivative and evaluated for their possible in vitro and in vivo anticancer activity. Methods: Herein we report the synthetic scheme which was followed for the preparation of a series of title compounds B1- B9 is outlined in the scheme 1. The intermediate 5-[(naphthalen-2- yloxy)methyl]-1,3,4-thiadiazolo-2-amine was prepared by heating 2-naphthoxyacetic acid and thiosemicarbazide in presence of phosphoryl chloride at a temperature of 65 - 750C. The obtained compound reacted with malononitrile and appropriate amount of aromatic and heteroaromatic aldehydes in refluxing ethanol yielded 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives (B1 – B9). The purity of synthesized compounds ensured by various spectral analysis. Results: In in-silico molecular docking studies compounds B3 and B9 show binding affinity like known PARP1 inhibitor olaparib. The cellular evaluation indicates that the anticancer activity of compounds B1, B3, B9 is significant when compared to standard drug (olaparib) against MDA-MB-232 cell line and compounds B3, B6, B7 are most active against MCF-7 cell lines. The most active compound B3 was subjected to acute oral toxicity studies by OECD 423 guidelines and in-vivo anti-cancer studies were carried out using DMBA induced model. Conclusion: The in-silico docking study of the newly synthesized compounds were performed, the results showed good binding mode in the active site of PARP1 enzyme. In-silico ADME properties of synthesized compounds were also studied and showed good drug like properties.

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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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Molecular docking studies of natural compounds of naringin on enzymes involved in the urea cycle pathway in hyperammonemia

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i5.19 ◽

2020 ◽

Vol 19 (5) ◽

pp. 1037-1043

Author(s):

Ramakrishnan Arumugam ◽

Renuka Mani ◽

Amalan Venkatesan ◽

Senthilmurugan Sengamalai ◽

Vijayakumar Natesan ◽

...

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Hydrogen Bonds ◽

Sodium Benzoate ◽

In Silico ◽

Urea Cycle ◽

Molecular Docking Study ◽

Standard Drug ◽

In Silico Studies ◽

Urea Cycle Enzymes

Purpose: To investigate the anti-hyperammonemic activity of naringin by molecular docking via in silico studies.Methods: Urea cycle proteins were docked to the natural compound naringin as well as a standard drug, sodium benzoate. Hydrogen bonds and binding energy were obtained using Catalytic Site Atlas and Cast P Finder Software Tool.Results: There were six urea cycle enzymes, including N-acetyl glutamate synthase, carbamoyl phosphate synthase I, ornithine transcarbamylase, argininosuccinate synthase, argininosuccinate lyase and arginase I. On evaluating protein interactions with naringin, which is dynamically connected to the urea cycle pathway with hyperammonemia, naringin showed more hydrogen bonds and also produced higher binding energy when compared to the standard drug, sodium benzoate.Conclusion: The results of the molecular docking study show that naringin interacts with urea cycle enzymes with more hydrogen bonds and higher bonding energy than the standard drug, sodium benzoate. This supports the hypothesis that naringin can prevent experimental hyperammonemia. Keywords: Naringin, Sodium benzoate, Hyperammonemia, Urea cycle enzymes, In silico studies

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

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200628104638 ◽

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.

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Synthesis, in silico studies and antibacterial activity of some novel 2-substituted benzimidazole derivatives

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-020-00144-9 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Ramakrishna Chintakunta ◽

Geethavani Meka

Keyword(s):

Antibacterial Activity ◽

Melting Point ◽

In Silico ◽

Software Tool ◽

Benzimidazole Derivatives ◽

Recrystallization Process ◽

Standard Drug ◽

In Silico Studies ◽

Drug Synthesis ◽

Percentage Absorption

Abstract Background The o-phenylenediamine is a versatile starting material for several compounds. Synthesized o-phenylenediamine and amino acids (glycine, alanine, aspartic acid, and l-proline) undergo condensation via Phillips reaction. The synthesized compound showed the promising antibacterial activity of Bacillus subtilis and Pseudomonas aeruginosa at the concentration of 100, 50, 25, 12.5, 6.25, 3.12, 1.6, 0.8, 0.4, and 0.2 μg/ml. Ciprofloxacin was used as standard drug. Synthesis of benzimidazole derivatives was carried out and purified by recrystallization process using ethanol. Substituted derivatives were characterized by melting point, TLC and spectroscopic methods include FT-IR and 1H-NMR. Results In silico studies were adopted for synthetic derivatives by Molinspiration, ChemDraw, and online software tool. Minimum inhibitory concentration (MIC) values of B. subtilis and P. aeruginosa were reported, and benzimidazole ligands and Molinspiration scores were generated and listed. Conclusion The more negative values indicate a higher binding affinity. The generated ligand observations can be visualized. Physical constants of synthesized derivates such as solubility and melting point were determined. Bioactivity scores were noted for different derivatives and predicted percentage absorption in the gut. The antibacterial activity was performed using the MIC method (aerobic).

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Structure-Based De Novo Design and Docking Studies of 5(S)-Methyl-L-Proline Containing Peptidomimetic Compounds as Dipeptidyl Peptidase-4 Inhibitors

Current Drug Discovery Technologies ◽

10.2174/1570163819666211221100457 ◽

2021 ◽

Vol 19 ◽

Author(s):

Anuradha K. Gajjar ◽

Chirag D. Pathak

Keyword(s):

Binding Sites ◽

De Novo ◽

Docking Study ◽

Dipeptidyl Peptidase ◽

Pharmacokinetic Studies ◽

Dipeptidyl Peptidase 4 ◽

Lipinski’S Rule ◽

Promising Therapeutic Approach ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Lipinski’S Rule Of Five

Background: Diabetes affects millions of people worldwide, with predicted numbers of about 700 million adults affected by 2045. Among the several anti-diabetic drug therapies available in the market, Dipeptidyl Peptidase-4 (DPP-4) inhibitors have emerged as a promising therapeutic approach with scope for exploration in the segment of peptidomimetics. Objective: Series of proline-containing peptidomimetic compounds were designed and investigated for their drug-likeness through Lipinski’s rule of five, lead-likeness through the rule of three, predictive pharmacokinetic studies (absorption, distribution, metabolism, and excretion), and toxicity properties through in-silico approaches. The designed compounds were evaluated for their interactions with binding sites of the enzyme DPP-4 using an extra precision docking approach. Methods: Proline-containing peptidomimetic compounds were designed rationally. Drug-likeness and lead-likeness properties were calculated using Schrödinger Maestro v11.2 software. ADME and toxicity properties were predicted using PreADMET version 2.0. Docking study was performed using Schrödinger Maestro v11.2 software, and ligands for the study were designed using MarvinSketch software. Results: 5(S)-methyl-L-proline containing 17 ligands were designed. All of them were found to obey Lipinski’s rule of five. Compounds were found to have good ADME profile and low toxicity predictions. Conclusion: Four compounds were found to have good interactions with DPP-4 binding sites and hence created the scope to develop a DPP-4 inhibitors containing 5(S)-methyl-L-proline moiety.

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In silico studies of bacterial derived fatty acid as a potential inhibitor of 1FGE and 1BQO

Research Journal of Biotechnology ◽

10.25303/1612rjbt119124 ◽

2021 ◽

Vol 16 (12) ◽

pp. 119-124

Author(s):

S. Syed Chandini ◽

Sairam Mantri

Keyword(s):

Ligand Binding ◽

Stearic Acid ◽

In Silico ◽

In Vivo Studies ◽

Binding Interaction ◽

Standard Drug ◽

Synthetic Drugs ◽

Potential Inhibitor ◽

In Silico Studies

Thrombomodulin (TM) and matrix metalloproteinase (MMPs) are the major factors that are responsible for lung cancer. Hence, the identification of novel compounds inhibiting TM and MMPs is the challenging task for the scientists. Even though synthetic drugs were developed, their toxicity and offtarget limit their usage. The current study aims to investigate the molecular simulations for bacterial derived stearic acid to estimate the in silico anticancer activity against TM and MMPs protein as target compounds and the findings were correlated with the standard drug vorinostat. Using Lamarckian genetic algorithm, the TM and MMPs were energy minimized and docked with stearic acid and vorinostat using auto dock 4.2 and visualized in PyMol software. Protein and ligand binding analysis revealed that stearic acid interacts with the amino acids of MMPs residues of PHE83, SER212, ALA213 and ASN214. It interacts with the TMs with two amino acid residues i.e. CYS407 and GLU408. Hence, compared to vorinostat, stearic acid shows a higher binding affinity towards MMPs and slightly lower affinity towards TM proteinase. We conclude that the computational analysis of ligand binding interaction of stearic acid suggests that it could be a potential inhibitor of matrix metallo proteinase and is effective against thrombomodulin and can be considered as an anticancer agent by in vivo studies.

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IN VITRO AND IN SILICO ALPHA-AMYLASE INHIBITION POTENTIAL (ANTI-DIABETIC ACTIVITY) OF PSEUDERANTHEMUM BICOLOR (SIMS) RADIK

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2020.v13i12.39824 ◽

2020 ◽

pp. 157-161

Author(s):

RAMESH BS ◽

LOKESH RAVI

Keyword(s):

Binding Energy ◽

Hydrogen Bonds ◽

Ethyl Acetate ◽

Bioactive Compounds ◽

Methyl Ether ◽

Docking Study ◽

Alpha Amylase ◽

Ligand Docking ◽

Standard Drug ◽

Reference Drug

Objective: Aim of this study is to evaluate theanti-diabetic activity of Pseuderanthemum bicolor commonly called limang-sugat by inhibiting alpha-amylase protein. Methods: Leaves of P. bicolor were extracted with methanol, chloroform, and ethyl acetate. The extracts were subjected for alpha-amylase inhibition assay and gas chromatography–mass spectrometry (GC–MS) analysis. Phytochemical compounds identified by GC-MS were subjected for protein-ligand docking study against alpha-amylase protein. Acarbose was used as a positive standard drug. Results: The major bioactive compounds obtained from methanol, chloroform, and ethyl acetate extracts were 1,6;2,3-Dianhydro-4-Deoxy-Beta-D-Ribo-Hexopyranose, Pseduosarsasapogenin-5,20-Dien, methyl ether/Hexatriacontane, Di-N-decylsulfone/Octadecanal, and squalene, respectively. A total of 19 secondary metabolites were subjected for protein–ligand docking study against the alpha-amylase protein. The reference drug acarbose demonstrated binding energy of −7.8 Kcal/mol and formed 20 hydrogen bonds with the enzyme. Acarbose signified high polar interaction with the amylase enzyme. Among the 19 test ligands, “2,2-Dibromocholestanone” from ethyl acetate extract exemplified the highest binding energy of −9.3 Kcal/mol. The next highest remarkable inhibition was showed by “Pseduosarsasapogenin-5,20-Dien Methyl Ether” present in the methanol extract, with a binding energy of -9.3 Kcal/mol with the formation of 2 hydrogen bonds. Conclusion: From the result, it could be concluded that the P. bicolor leaves contain various bioactive compounds which are considered as a good anti-diabetic drug.

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