MOLECULAR DOCKING STUDY ON 1H-(3,4d) PYRAZOLO-PYRIMIDINES AS CYCLIN DEPENDANT KINASE (CDK2) INHIBITORS

Objective: CDK2 inhibitors are implicated in several carcinomas viz. Carcinoma of lung, bladder, sarcomas and retinoblastoma. Pyrazolopyrimidines, being purine bioisosters inhibit more than one type of kinase. In this study, we are studying some novel derivatives of 1H-pyrazolo [3,4d] pyrimidines not reported earlier. The objective of the present study is an attempt towards design and development of 1H-[3,4-] pyrazolo-pyrimidines as CDK2 inhibitors through rational drug design.Methods: The present study has been done on CDK2 structure, PDB ID, 3WBL, co-crystallized with ligand PDY from RCSB protein data bank. A series of seventeen 1H-Pyrazolo [3,4-d] pyrimidines feasible for synthesis was docked on the said CDK2 receptor using Auto Dock 4 version, 1.5.6. Outputs were exported to discovery studio 3.5 client for visual inspection of the binding modes and interactions of the compounds with amino acid residues in the active sites.Results: The results of docking studies revealed that the present series of 1H-Pyrazolo[3,4-d] pyrimidines is showing significant binding through hydrogen bonding, hydrophobic, pi and Van der waals interactions, similar to the ligand PDY. Some conserved H-bond interactions comparable to bioisosters and compounds presently under human trials were noted. Ki values predicted in silico also suggest that the series will show promising CDK2 inhibitory activity.Conclusion: The series designed and docked can be further developed by synthesis and in vitro and in vivo activity. The receptor inhibitory activity can also be checked by specific receptor assays.

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Potential Bioactive glycosylated flavonoids as SARS-CoV-2 Main protease Inhibitors: A molecular Docking Study

10.31219/osf.io/k4h5f ◽

2020 ◽

Author(s):

sabri ahmed cherrak ◽

merzouk hafida ◽

mokhtari soulimane nassima

Keyword(s):

Molecular Docking ◽

Data Bank ◽

Docking Study ◽

Docking Studies ◽

Molecular Docking Study ◽

Chemical Structures ◽

In Vivo Experiments ◽

Main Protease

A novel (COVID-19) responsible of acute respiratory infection closely related to SARS-CoV has recently emerged. So far there is no consensus for drug treatment to stop the spread of the virus. Discovery of a drug that would limit the virus expansion is one of the biggest challenges faced by the humanity in the last decades. In this perspective, testing existing drugs as inhibitors of the main COVID-19 protease is a good approach.Among natural phenolic compounds found in plants, fruit, and vegetables; flavonoids are the most abundant. Flavonoids, especially in their glycosylated forms, display a number of physiological activities, which makes them interesting to investigate as antiviral molecules.The flavonoids chemical structures were downloaded from PubChem and protease structure 6lu7 was from the Protein Data Bank site. Molecular docking study was performed using AutoDock Vina. Among the tested molecules Quercetin-3-O-rhamnoside showed the highest binding affinity (-9,7 kcal/mol). Docking studies showed that glycosylated flavonoids are good inhibitors for the covid-19 protease and could be further investigated by in vitro and in vivo experiments for further validation.

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Molecular Docking Study of COVID-19 Main Protease with Clinically Approved Drugs

10.26434/chemrxiv.12318689.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

TACHOUA Wafa ◽

KABRINE Mohamed

Keyword(s):

Docking Study ◽

Docking Studies ◽

Binding Modes ◽

Molecular Docking Study ◽

In Vivo Evaluation ◽

Binding Cavity ◽

Approved Drugs ◽

Potential Inhibitors

A novel strain of coronavirus, namely, Corona Virus Infection Disease 19 has been identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor we performed docking studies on the main virus protease with eight drugs belonging to four pharmacological classes: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. These two compounds revealed a minimum binding energy of -8.87 and -8.71 Kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Lymecycline and Mizolastine interact with specific residues in substrate binding cavity. Thus, Lymecycline and Mizolastione may serve as a tool to fight COVID-19 disease. However, this data need further in vitro and in vivo evaluation to repurpose these two drugs against COVID-19 disease.

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Design, Synthesis, Molecular Docking Study and Anti-Hepatocellular Carcinoma Evaluation of New Bis-Triazolothiadiazines

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666191015130037 ◽

2020 ◽

Vol 20 (9) ◽

pp. 788-800 ◽

Cited By ~ 2

Author(s):

Sobhi M. Gomha ◽

Zeinab A. Muhammad ◽

Elham Ezz El-Arab ◽

Amira M. Elmetwally ◽

Abdelaziz A. El-Sayed ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Docking ◽

Docking Study ◽

Docking Studies ◽

Binding Modes ◽

Molecular Docking Study ◽

Design Synthesis ◽

Reference Drug ◽

Ic50 Value

Objective: The reaction of bis(4-amino-4H-1,2,4-triazole-3-thiol) with hydrazonoyl halides and α-halo-ketones gave a new series of bis-1,2,4-triazolo[3,4-b]thiadiazine derivatives. Methods: The structure of the new products was established on the basis of their elemental and spectral data (mass, 1H NMR, 13C NMR and IR) and an alternate method. Results: Several of the synthesized products were subjected to in vitro anticancer screening against human hepatocellular carcinoma (HepG-2) and the results showed that compounds 16, 14 and 12 have promising activities (IC50 value of 24.8±9.1, 28.3±0.5, and 31±2.9μM, respectively) compared with Harmine reference drug (IC50 value of 22.4±1.11 μM). Conclusion: Moreover, molecular docking studies were performed to analyze the binding modes of the discovered hits into the active site of DYRK1A using iGEMDOCK.

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Computational Evaluation of the Inhibition Efficacies of HIV Antivirals on SARS-CoV-2 (COVID-19) Protease and Identification of 3D Pharmacophore and Hit Compounds

Advances in Pharmacological and Pharmaceutical Sciences ◽

10.1155/2020/8818008 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Vinod P. Raphael ◽

Shaju K. Shanmughan

Keyword(s):

Data Bank ◽

Docking Studies ◽

Hiv Treatment ◽

Molecular Structures ◽

Crystallographic Structure ◽

Discovery Studio ◽

3D Pharmacophore ◽

Toxicological Studies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus behind the fast-spreading coronavirus disease 2019 (COVID-19). Pharmaceutical researchers are currently researching medications or preventive vaccines that may be used to treat and combat the spread of COVID-19. Health practitioners all over the world are treating patients with currently available antiviral drugs, primarily the protease inhibitors used for HIV treatment. The present study mainly aims to evaluate the potencies of eight anti-HIV drugs to inhibit coronavirus protease using in silico methods. Derivation of pharmacophore, identification of hit molecules, and checking their virtual inhibition efficacies on the COVID-19 protease were also carried out in the present investigation. Classification of eight drug molecules (atazanavir, darunavir, fosamprenavir (amprenavir—metabolised product), saquinavir, lopinavir, ritonavir, nelfinavir, and indinavir) based on their molecular structures was completed and reported. The X-ray crystallographic structure of the main protease of coronavirus (SARS-CoV-2 protease) was obtained from the Protein Data Bank and prepared for computational studies using Edu PyMOL software. Docking studies were performed with AutoDock Vina software, and the results were evaluated with Discovery Studio software. The binding scores of the drugs on protease followed the order saquinavir > nelfinavir > lopinavir = indinavir > darunavir > amprenavir > ritonavir > atazanavir. Web servers such as PharmaGist and ZINCPharmer were employed to derive the 3D pharmacophore and to identify potential hit compounds, respectively. The identified hit molecules were docked with the SARS-CoV-2 protease and analysed. A detailed account of the type of interaction between the protease and the molecules is discussed. The majority of hit compounds displayed appreciable binding affinities on coronavirus protease. Three hit compounds possess structures similar to that of natural products, viz., flavonoids, and nucleoside. These molecules were hydrophilic and slightly deviated from Lipinski parameters. All other derived molecules obeyed the Lipinski rule. In vitro, in vivo, and toxicological studies of these compounds have to be performed before checking the actual druggability of these compounds.

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An insight on safety, efficacy, and molecular docking study reports of N-acetylcysteine and its compound formulations

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2020-0099 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Laiba Rind ◽

Mohammad Ahmad ◽

Mohammad Irfan Khan ◽

Badruddeen ◽

Juber Akhtar ◽

...

Keyword(s):

Molecular Docking ◽

Analytical Techniques ◽

Docking Study ◽

Biological Properties ◽

Docking Studies ◽

Pharmaceutical Product ◽

Fixed Dose ◽

Molecular Docking Study

Abstract N-acetylcysteine (NAC) is considered as the body’s major antioxidant molecules with diverse biological properties. In this review, the pharmacokinetics, safety and efficacy report on both the preclinical and clinical summary of NAC is discussed. Both in vitro and in vivo preclinical studies along with the clinical data have shown that NAC has enormous biological properties. NAC is used in the treatment of acetaminophen poisoning, diabetic nephropathy, Alzheimer’s disease, schizophrenia, and ulcerative colitis, etc. Numerous analytical techniques, for instance, UPLC, LC-MS, HPLC, RP-IPC are primarily employed for the estimation of NAC in different single and fixed-dose combinations. The molecular docking studies on NAC demonstrate the binding within Sudlow’s site-I hydrogen bonds and formation of NAC and BSA complexes. Various hydrophobic and hydrophilic amino acids generally exist in making contact with NAC as NAC-BSA complexes. Docking studies of NAC with the active site of the urease exposed an O-coordinated bond through nickel 3002 and a hydrogen bond through His-138. NAC and its analogs also made the allosteric pockets that helped to describe almost all favorable pose for the chaperone in a complex through the protein. Thus, we intended to highlight the several health benefits of this antioxidant compound and applications in pharmaceutical product development.

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MOLECULAR DOCKING AND SCREENING OF DRUGS FOR 6LU7 PROTEASE INHIBITOR AS A POTENTIAL TARGET FOR COVID-19

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2022v14i1.43132 ◽

2022 ◽

pp. 100-105

Author(s):

MANOJ GADEWAR ◽

BHARAT LAL

Keyword(s):

Molecular Docking ◽

Data Bank ◽

Docking Study ◽

In Vivo Studies ◽

Molecular Docking Study ◽

Potential Target ◽

Novel Coronavirus ◽

Potential Inhibitors

Objective: The aim of present investigation is docking of various existing antiviral, anti-tubercular and anti-malarial drugs on 6LU7 receptor of SARS-CoV-2 in the treatment of COVID-19. Methods: In this study, the structure of coronavirus binding protein and ligands for various drugs were collected from the protein data bank and pub chem. Molecular docking was carried out using Schrodinger 9.0 software. In molecular docking study, 19 different drugs of various categories like antiviral, anti-malarial and anti-tubercular were investigated for analyzing binding to 6LU7 receptors of COVID-19. Results: The docking result showed a high affinity of zanamivir, montelukast, ramdesvir, ritonavir, cobicistat and favipravir to the 6LU7 receptor of novel coronavirus. Thus the combination of these drugs may be useful in preventing further infection and can be used as a potential target for further in vitro and in vivo studies of SARS-CoV-2. Conclusion: Treatment of COVID-19 has been challenge due to the non-availability of effective drug therapy. In this study, we reported drugs for targeting 6LU7 Mpro/3Clpro protein, which showed prominent effects as potential inhibitors of COVID-19 Mpro.

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Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug

Pharmaceuticals ◽

10.3390/ph14070685 ◽

2021 ◽

Vol 14 (7) ◽

pp. 685

Author(s):

Sandra Amanda Kozieł ◽

Monika Katarzyna Lesiów ◽

Daria Wojtala ◽

Edyta Dyguda-Kazimierowicz ◽

Dariusz Bieńko ◽

...

Keyword(s):

Molecular Docking ◽

Serum Proteins ◽

Docking Study ◽

Minor Groove ◽

Docking Studies ◽

Minor Groove Binding ◽

Binding Modes ◽

Groove Binding ◽

Molecular Docking Study ◽

Threading Intercalation

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues.

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Characterization of Possible α-Glucosidase Inhibitors from Trigonella stellata Extract Using LC–MS and In Silico Molecular Docking

Plants ◽

10.3390/plants11020208 ◽

2022 ◽

Vol 11 (2) ◽

pp. 208

Author(s):

Ahlam Elwekeel ◽

Dalia El Amir ◽

Enas I. A. Mohamed ◽

Elham Amin ◽

Marwa H. A. Hassan ◽

...

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Docking Studies ◽

Antidiabetic Activity ◽

Flavonoid Glycosides ◽

Total Phenolic ◽

Cytotoxic Activities ◽

Alcoholic Extract ◽

Molecular Docking Study

The current study accentuates the significance of performing the multiplex approach of LC-HRESIMS, biological activity, and docking studies in drug discovery, taking into consideration a review of the literature. In this regard, the investigation of antioxidant and cytotoxic activities of Trigonella stellata collected from the Egyptian desert revealed a significant antioxidant capacity using DPPH with IC50 = 656.9 µg/mL and a moderate cytotoxicity against HepG2, MCF7, and CACO2, with IC50 values of 53.3, 48.3, and 55.8 µg/mL, respectively. The evaluation of total phenolic and flavonoid contents resulted in 32.8 mg GAE/g calculated as gallic acid equivalent and 5.6 mg RE/g calculated as rutin equivalent, respectively. Chemical profiling of T. stellata extract, using LC-HRESIMS analysis, revealed the presence of 15 metabolites, among which eleven compounds were detected for the first time in this species. Interestingly, in vitro testing of the antidiabetic activity of the alcoholic extract noted an α-glucosidase enzyme inhibitory activity (IC50 = 559.4 µg/mL) better than that of the standard Acarbose (IC50 = 799.9 µg/mL), in addition to a moderate inhibition of the α-amylase enzyme (IC50 = 0.77 µg/mL) compared to Acarbose (IC50 = 0.21 µg/mL). α-Glucosidase inhibition was also virtualized by binding interactions through the molecular docking study, presenting a high binding activity of six flavonoid glycosides, as well as the diterpenoid compound graecumoside A and the alkaloid fenugreekine. Taken together, the conglomeration of LC-HRESIMS, antidiabetic activity, and molecular docking studies shed light on T. stellata as a promising antidiabetic herb.

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Synthesis, Characterization, in vitro Antimicrobial Evaluation and in silico Molecular Docking and ADME Prediction of 4-Chlorophenyl Furfuran Derivatives bearing Pyrazole Moieties

Asian Journal of Chemistry ◽

10.14233/ajchem.2020.22634 ◽

2020 ◽

Vol 32 (6) ◽

pp. 1482-1490

Author(s):

Manju Mathew ◽

Raja Chinnamanayakar ◽

Ezhilarasi Muthuvel Ramanathan

Keyword(s):

Molecular Docking ◽

In Silico ◽

Docking Study ◽

Docking Studies ◽

Moderate Activity ◽

Molecular Docking Study ◽

Adme Prediction ◽

Antimicrobial Studies ◽

In Silico Molecular Docking

A series of 1-(5-(5-(4-chlorophenyl)furan-2-yl)-4,5-dihyropyrazol-1-yl ethanone (5a-h) was synthesized through E-(3-(5-(4-chloro-phenyl)furan-2-yl)-1-phenylprop-2-en-1-one (3a-h) with hydrazine monohydrate and sodium acetate. Totally, eight compounds were synthesized and their structures were elucidated by infrared, 1H & 13C NMR, elemental analysis, antimicrobial studies, in silico molecular docking studies and also in silico ADME prediction. Antimicrobial studies of the synthesized compounds showed good to moderate activity against the all the stains compared with standard drugs. in silico Molecular docking study was carried out using bacterial protein and BC protein. Synthesized compounds (5a-h) showed good docking score compared with ciprofloxacin. Antimicrobial study was carried out for 4-chlorophenyl furfuran pyrazole derivatives (5a-h). The results of assessment of toxicities, drug likeness and drug score profiles of compounds (5a-j) are promising

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Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

10.26434/chemrxiv.12179202 ◽

2020 ◽

Author(s):

pooja singh ◽

Angkita Sharma ◽

Shoma Paul Nandi

Keyword(s):

Molecular Docking ◽

Antiviral Drug ◽

Cyclopiazonic Acid ◽

Docking Study ◽

Molecular Docking Study ◽

Docking Score ◽

Protease Enzyme ◽

Main Protease

Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease Mpro, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in Aspergillus flavus and Aspergillus oryzae fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth in- vitro and in-vivo.

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