scholarly journals Rational in silico drug design of HIV-RT inhibitors through G-QSAR and molecular docking study of 4-arylthio and 4-aryloxy-3-iodopyridine-2(1-H)-one derivative

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Debadash Panigrahi ◽  
Amiyakanta Mishra ◽  
Susanta Kumar Sahu
Keyword(s):  
Molecular Docking ◽  
Reverse Transcriptase ◽  
Active Site ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Immunodeficiency Virus ◽  
Qsar Models ◽  
Hiv Rt ◽  
Rt Inhibitors ◽  
Anti Hiv

Abstract Background Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV). Antiretroviral therapy (ART) against HIV infection offers the promise of controlling disease progression and prolonging the survival of HIV-infected patients. Reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In this direction, by using group-based QSAR study (G-QSAR), identification of the structural need for the development of lead structure with reverse transcriptase inhibition on 97 reported structures was carried out. Docking analysis was performed further and suggested the structural properties required for binding affinity with the receptor. The molecules in the data set were fragmented into six (R1, R2, R3, R4, R5, and R6) by applying the fragmentation pattern. Three G-QSAR models were selected based on the statistical significance of the model. The molecular docking study was performed to explain the structural properties required for the design of potent HIV-RT inhibitors. Results The statistically validated QSAR models reveal the presence of higher hydrophobic groups containing single-bonded –Br atom, 2 aromatic bonded –NH group with less electronegativity, and entropic interaction fields at R2 essential for better anti-HIV activity. The presence of a lipophilic group at R3, oxygen and sulfur connected with two aromatic bonds at R4, and –CH3 group at R5 was fruitful for reverse transcriptase inhibition. Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond, Van der Waal’s, charge, aromatic, and π–π interactions with residues present at the active site. Conclusion The results of the generated models provide significant site-specific insight into the structural requirements for reverse transcriptase inhibition during the design and development of novel anti-HIV compounds. Molecular docking study revealed the binding interaction between the ligand and the receptor which gave insight towards the structure-based design for the discovery of more potent compounds with better activity against HIV infection.

Benzothiazol Clubbed Imidazol-4-ones as Anti-fungal, Anti-tubercular and Anti-HIV-1 Agents: Their Synthesis and Molecular Docking Study

2019 ◽  
Vol 16 (4) ◽  
pp. 382-391
Author(s):  
Navin B. Patel ◽  
Asif R. Shaikh ◽  
Vatsal M. Patel ◽  
Edgar E. Lara-Ramirez ◽  
Gildardo Rivera
Keyword(s):  
Molecular Docking ◽  
Reverse Transcriptase ◽  
Docking Study ◽  
Antimicrobial Activities ◽  
Spectral Studies ◽  
Molecular Docking Study ◽  
Broth Microdilution Method ◽  
Anti Hiv ◽  
Hiv 1

Background: The present work describes antimicrobial, antimycobacterium and anti HIV-1 evaluation of newly synthesized 5-(4-Substituted-benzylidene)-3-[4-(5-methyl-benzothiazol- 2-yl)-phenyl]-2-phenyl-3,5-dihydro-imidazol-4-one (4a-o). The docking studies were performed in order to predict the potential binding affinities. Objective: The major aim of this study is to develop the new class of bezylidine candidate clubbed with benzothiazole with less toxicity and improved potency as antimicrobial, antitubercular and anti HIV-1. Methods: The titled compounds were characterized by spectral studies (IR, 1H NMR, 13C NMR and Mass). In vitro antimycobacterium activity was carried out using Lowenstein-Jensen medium method and antimicrobial activity using the broth microdilution method. The anti HIV-1 reverse transcriptase activity was determined by the colorimetric MTT method and inhibition of virusinduced cytopathogenicity in MT-4 cells. Results: Compound 4i (50 µM) showed better antifungal activity against A. clavatus. Compound 4g (50 µM) with 95% inhibition demonstrated good activity against M. tuberculosis H37Rv. Compound 4k showed CC50 (50 µM) against MT-4 (CD4+ Human T-cells containing an integrated HTLV-1 genome) cells by 50%, while 16 µM concentration value EC50 from the HIV-1 induced cytopathogenicity. Molecular docking study suggested that 4k interacted with the target with binding energy by Vina score (-10.3 Kcal/mol). Conclusion: The preliminary in vitro evaluation results revealed that some of the compounds have promising antimicrobial activities as well as antitubercular potency. Among the various substituents on benzylidene, the nitro group was the most beneficial for improving the anti-HIV-1 activity. Docking result suggested that 4k compound could be acting as a non-competitive or weak inhibitor of Reverse Transcriptase (RT).

A Combined approach of Pharmacophore Modeling, QSAR Study, Molecular Docking and in silico ADME/Tox prediction of 4-Arylthio & 4- Aryloxy-3- Iodopyridine-2(1H)-one analogs to identify potential Reverse Transcriptase inhibitor: Anti-HIV agents

2020 ◽  
Vol 17 ◽  
Author(s):  
Debadash Panigrahi ◽  
Amiyakanta Mishra ◽  
Susanta Kumar Sahu ◽  
Mohd. Afzal Azam ◽  
C.M. Vyshaag
Keyword(s):  
Molecular Docking ◽  
Reverse Transcriptase ◽  
Active Site ◽  
3D Qsar ◽  
Qsar Model ◽  
Pharmacophore Modeling ◽  
Reverse Transcriptase Inhibitors ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Exclusion Method

Background: Reverse transcriptase is an important therapeutic target to treat AIDS caused by the Human Immunodeficiency Virus (HIV). Despite many effective anti-HIV drugs, reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In the present work, we have expedited the use of different computational modules and presented an easy, cost-effective and high throughput screening method to identify potential reverse transcriptase inhibitors. Methods: A congeneric series of 4-Arylthio & 4-Aryloxy-3- Iodopyridine-2(1H)-one analogs having anti-HIV activity were subjected to structure-based 2D, 3D QSAR, Pharmacophore Modeling, and Molecular Docking to elucidate the structural properties required for the design of potent HIV-RT inhibitors. Prediction of preliminary Pharmacokinetic and the Drug Likeliness profile was performed for these compounds by in silico ADME study. Results: The 2D and 3D- QSAR models were developed by correlating two and three-dimensional descriptors with activity (pIC50) by sphere exclusion method and k-nearest neighbor molecular field analysis approach, respectively. The significant 2D- QSAR model developed by Partial Least Square associated with the Sphere Exclusion method (PLS-SE) having r2 and q2 values 0.9509 and 0.8038 respectively. The 3D-QSAR model by Step Wise variable selection method (SW-kNN MFA) is more significant which has a cross-validated squared correlation coefficient q2= 0.8509 and a non-cross-validated correlation coefficient pred_r2= 0.8102. The pharmacophore hypothesis was developed which comprised 5 features includes 3 aliphatic regions (Ala), 1 H-bond donor (HDr) and 1 H-bond acceptor (HAc). Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond and π - π interaction with LYS-101, LYS-103, TYR- 181, TYR-188 and TRP-229 residues present at the active site. All the candidates with good bioavailability and ADMET drug likeliness properties. Conclusion: The results of the present work provide more useful information and important structural insights for the discovery, design of novel and potent reverse transcriptase inhibitors with high therapeutic windows in the future.

scholarly journals New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

2019 ◽  
Vol 20 (20) ◽  
pp. 5209 ◽  
Author(s):  
Elwira Chrobak ◽  
Krzysztof Marciniec ◽  
Aleksandra Dąbrowska ◽  
Paweł Pęcak ◽  
Ewa Bębenek ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antiviral Effect ◽  
Docking Study ◽  
Strong Interactions ◽  
Molecular Docking Study ◽  
Gag Protein ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3′,3′-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 μM and 0.03 μM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

2020 ◽  
Vol 16 (7) ◽  
pp. 892-902 ◽  
Author(s):  
Aida Iraji ◽  
Mahsima Khoshneviszadeh ◽  
Pegah Bakhshizadeh ◽  
Najmeh Edraki ◽  
Mehdi Khoshneviszadeh
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Competitive Inhibition ◽  
Docking Study ◽  
Biological Evaluation ◽  
Primary Response ◽  
Ratio Method ◽  
Molecular Docking Study ◽  
Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti– tyrosinase agents. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

scholarly journals Screening of potential anti-HIV compounds from Achyranthes aspera extracts for SARS-CoV-2: An insight from molecular docking study

2021 ◽  
Vol 1797 (1) ◽  
pp. 012042
Author(s):  
Tanmoy Dutta ◽  
Sajal Ghorai ◽  
Abdul Ashik Khan ◽  
Nabajyoti Baildya ◽  
Narendra Nath Ghosh
Keyword(s):  
Molecular Docking ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Achyranthes Aspera ◽  
Anti Hiv

scholarly journals Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2291 ◽  
Author(s):  
David Malinak ◽  
Eugenie Nepovimova ◽  
Daniel Jun ◽  
Kamil Musilek ◽  
Kamil Kuca
Keyword(s):  
Molecular Docking ◽  
Molecular Modelling ◽  
Active Site ◽  
Molecular Design ◽  
Docking Study ◽  
The Novel ◽  
Molecular Docking Study ◽  
Causal Treatment ◽  
Modelling Study

The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator’s molecule are described.

Anti-HIV-1 Integrase Activity and Molecular Docking Study of Compounds from Caesalpinia  sappan L.

2015 ◽  
Vol 29 (5) ◽  
pp. 724-729 ◽  
Author(s):  
Supinya Tewtrakul ◽  
Prapaporn Chaniad ◽  
Somsak Pianwanit ◽  
Chatchanok Karalai ◽  
Chanita Ponglimanont ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Caesalpinia Sappan ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Identification of Compounds from Nigella Sativa as New Potential Inhibitors of 2019 Novel Coronasvirus (Covid-19): Molecular Docking Study.

2020 ◽  
Author(s):  
Salim Bouchentouf ◽  
Noureddine Missoum
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Nigella Sativa ◽  
Specific Treatment ◽  
Docking Study ◽  
Clinical Test ◽  
Molecular Docking Study ◽  
Great Opportunity ◽  
Drug Candidates ◽  
Energy Score

<p>The spread of the global COVID-19 pandemic, the lack of specific treatment and the urgent situation requires use of all resources to remedy this scourge. In the present study, using molecular docking, we identify new probable inhibitors of COVID-19 by molecules from <i>Nigella sativa L</i>, which is highly reputed healing herb in North African societies and both Islamic and Christian traditions. The discovery of the M<sup>pro</sup> protease structure in COVID-19 provides a great opportunity to identify potential drug candidates for treatment. Focusing on the main proteases in CoVs (3CL<sup>pro</sup>/M<sup>pro</sup>) (PDB ID 6LU7 and 2GTB); docking of compounds from <i>Nigella Sativa</i> and drugs under clinical test was performed using Molecular Operating Environment software (MOE). Nigelledine docked into 6LU7 active site gives energy complex about -6.29734373 Kcal/mol which is close to the energy score given by chloroquine (-6.2930522 Kcal/mol) and better than energy score given by hydroxychloroquine (-5.57386112 Kcal/mol) and favipiravir (-4.23310471 kcal/mol). Docking into 2GTB active site showed that α- Hederin gives energy score about-6.50204802 kcal/mol whcih is better energy score given by chloroquine (-6.20844936 kcal/mol), hydroxychloroquine (-5.51465893 kcal/mol)) and favipiravir (-4.12183571kcal/mol). Nigellidine and α- Hederin appeared to have the best potential to act as COVID-19 treatment. Further, researches are necessary to testify medicinal use of identified and to encourage preventive use of <i>Nigella Sativa </i>against coronavirus infection.</p>

scholarly journals MOLECULAR DOCKING STUDY TO IDENTIFY POTENTIAL INHIBITOR OF COVID-19 MAIN PROTEASE ENZYME: AN IN-SILICO APPROACH

2020 ◽  
Author(s):  
Anurag Agrawal ◽  
Nem Kumar Jain ◽  
Neeraj Kumar ◽  
Giriraj T Kulkarni
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Potential Threat ◽  
Discovery Studio ◽  
Chemical Structures ◽  
Potential Inhibitor ◽  
Protease Enzyme ◽  
Main Protease

This study belongs to identification of suitable COVID-19 inhibitors<br><div><br></div><div>Coronavirus became pandemic very soon and is a potential threat to human lives across the globe. No approved drug is currently available therefore an urgent need has been developed for any antiviral therapy for COVID-19. For the molecular docking study, ten herbal molecules have been included in the current study. The three-dimensional chemical structures of molecules were prepared through ChemSketch 2015 freeware. Molecular docking study was performed using AutoDock 4.2 simulator and Discovery studio 4.5 was employed to predict the active site of target enzyme. Result indicated that all-natural molecules found in the active site of enzyme after molecular docking. Oxyacanthine and Hypericin (-10.990 and -9.05 and kcal/mol respectively) have shown good binding efficacy among others but Oxyacanthine was the only natural product which made some of necessary interactions with residues in the enzyme require for target inhibition. Therefore Oxyacanthine may be considered to be potential inhibitor of main protease enzyme of virus but need to be explored for further drug development process. <br></div>

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