Synthesis, Antitubercular Activity, Molecular Modeling and Docking Studies of Novel Thiazolidin-4-One Linked Dinitrobenzamide Derivatives

2020 ◽  
Vol 16 (1) ◽  
pp. 64-71
Author(s):  
Karanveer Singh ◽  
Manish Sinha ◽  
Shruti Kuletha ◽  
Baljeet Kaur ◽  
Amandeep Kaur ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Molecular Modeling ◽  
Antitubercular Activity ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Lead Optimization ◽  
World Health ◽  
Aromatic Moiety ◽  
Hydrogen Bond Interactions ◽  
The World

Background: Tuberculosis is a catastrophe sprawled across the world. The World Health Organization Global Tuberculosis Report 2017 inferred that there were an estimated 10.4 million people suffered from tuberculosis including 490000 Multidrug-Resistant TB (MDR-TB) cases. Several new lead molecules like dinitrobenzamide derivatives were found to be highly active against multidrugresistant strains of M. tuberculosis. To further explore the pharmacophoric space around the dinitobenzamide moiety, a series of compounds have been synthesized by linking it with the thiazolidin- 4-one. The presented work is an effort to study the biological effect of thiazolidin-4-one scaffold on dinitrobenzamide derivatives as antitubercular agents. A molecular modeling study was also performed on the synthesized molecules to reveal the requirements for further lead optimization. Methods: The thiazolidin-4-one linked 3,5-dinitrobenzamide derivatives have been synthesized by onepot three-component condensation reaction of an amine, substituted aldehydes and thioglycolic acid in presence of N, N'-Dicyclohexylcarbodiimide (DCC). These compounds were evaluated against Mycobacterium tuberculosis H37Ra. A pharmacophore modeling approach has been used in order to explore the collection of possible pharmacophore queries of thiazolidin-4-one linked 3, 5-dinitrobenzamide derivatives against M. tuberculosis. The synthesized compounds were docked on to the M. tuberculosis DprE1 enzyme to identify the structural features requirement of these analogs against this potential target of M. tuberculosis. Results: The synthesized compounds showed the antitubercular activity in the range of 6.25-50 μg/ml. The pharmacophore modeling suggests that the presence of aromatic moiety, thiazolidin-4-one ring and one of the nitro groups are significant for inhibiting the enzymatic activity. While docking studies showed that hydrophobic and hydrogen bond interactions of the aromatic moiety and nitro group crucial to inactivate the DprE1 enzyme. Conclusion: The study showed that the linking of thiazolidin-4-one with dinitrobenzamide leads to compounds active against M. tuberculosis. These findings also suggested that further lead optimization would be carried out by focusing on the aromatic system along with electron-rich substituents placed on the thiazolidin-4-one for making better hydrophobic and hydrogen bond interactions with the DprE1 target.

scholarly journals Anti-inflammatory, antiallergic and COVID-19 protease inhibitory activities of phytochemicals from the Jordanian hawksbeard: identification, structure–activity relationships, molecular modeling and impact on its folk medicinal uses

RSC Advances ◽  
2020 ◽  
Vol 10 (62) ◽  
pp. 38128-38141
Author(s):  
Sherif S. Ebada ◽  
Nariman A. Al-Jawabri ◽  
Fadia S. Youssef ◽  
Dina H. El-Kashef ◽  
Tim-Oliver Knedel ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
World Health Organization ◽  
World Health ◽  
Medicinal Uses ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
The World ◽  
Inhibitory Activities ◽  
Novel Coronavirus ◽  
Health Organization

On Wednesday 11th March, 2020, the world health organization (WHO) announced novel coronavirus (COVID-19, also called SARS-CoV-2) as a pandemic.

Identification of new checkpoint kinase-1 (Chk1) inhibitors by docking, 3D-QSAR, and pharmacophore-modeling methods

2012 ◽  
Vol 90 (8) ◽  
pp. 675-692 ◽  
Author(s):  
Premlata K. Ambre ◽  
Raghuvir R. S. Pissurlenkar ◽  
Evans C. Coutinho ◽  
Radhakrishnan P. Iyer
Keyword(s):  
Hydrogen Bond ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bond Acceptor ◽  
Checkpoint Kinase ◽  
Checkpoint Kinase 1 ◽  
Qsar Models ◽  
Potential Inhibitors

Inhibition of checkpoint kinase-1 (Chk1) by small molecules is of great therapeutic interest in the field of oncology and for understanding cell-cycle regulations. This paper presents a model with elements from docking, pharmacophore mapping, the 3D-QSAR approaches CoMFA, CoMSIA and CoRIA, and virtual screening to identify novel hits against Chk1. Docking, 3D-QSAR (CoRIA, CoMFA and CoMSIA), and pharmacophore studies delineate crucial site points on the Chk1 inhibitors, which can be modified to improve activity. The docking analysis showed residues in the proximity of the ligands that are involved in ligand–receptor interactions, whereas CoRIA models were able to derive the magnitude of these interactions that impact the activity. The ligand-based 3D-QSAR methods (CoMFA and CoMSIA) highlight key areas on the molecules that are beneficial and (or) detrimental for activity. The docking studies and 3D-QSAR models are in excellent agreement in terms of binding-site interactions. The pharmacophore hypotheses validated using sensitivity, selectivity, and specificity parameters is a four-point model, characterized by a hydrogen-bond acceptor (A), hydrogen-bond donor (D), and two hydrophobes (H). This map was used to screen a database of 2.7 million druglike compounds, which were pruned to a small set of potential inhibitors by CoRIA, CoMFA, and CoMSIA models with predicted activity in the range of 8.5–10.5 log units.

scholarly journals Bioinformatic study to discover natural molecules with activity against COVID-19

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1203
Author(s):  
Sweta Singh ◽  
Hector Florez
Keyword(s):  
Docking Studies ◽  
Benzyl Ester ◽  
The Other ◽  
World Health ◽  
Drug Candidate ◽  
The World ◽  
Bioinformatics Study ◽  
Health Organization ◽  
Inhibitory Drug ◽  
Quillaic Acid

Background: In 2020, the world has struggled to deal with coronavirus disease 2019 (COVID-19), which started in 2019 in China and has spread throughout the globe, affecting at least 31,175,835 humans globally and claiming 962,634 lives reported till 22nd September, 2020 by the World Health Organization. The main causative agent for this disease is known as severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). So far, there is no cure or proven therapeutics available till date. Therefore, we undertook this study to find the most probable drug candidate through a bioinformatics study. Methods: Thus, we virtually screened the Zinc natural database using HTVS tool through molecular docking studies to analyze molecules recommended for the treatment of COVID-19. Results: Ramipril benzyl ester, propafenone dimer and Lariciresinol are three important drugs found from the present study due to their medicinal application which could be helpful in treating the disease. Stylopine, quillaic acid, cinobufagin, vitisinol C, segetalin A, scopolamine, 3-oxo glycyrrhetinic acid, conchinone B, lactimidomycin and cardinalins 4 are the other lead molecules that could be used as therapeutics against COVID-19 disease. Conclusions: The studied molecules could act as an effective inhibitory drug against COVID-19.

scholarly journals IN SILICO DESIGN OF POTENTIAL 1, 5-BENZOTHIAZEPINE DERIVATIVES AS AN ANTI - CONVULSANT AGENT BY MOLECULAR DOCKING STUDIES

2019 ◽  
pp. 29-36
Author(s):  
Parjane Smita ◽  
Kunkulol Rahul ◽  
Nandal Dattatray
Keyword(s):  
Hydrogen Bond ◽  
Docking Studies ◽  
Hydrogen Bond Interaction ◽  
Docking Analysis ◽  
Hydrogen Bond Interactions ◽  
Binding Score ◽  
Anticonvulsant Agent ◽  
Significant Area ◽  
Patients With Epilepsy ◽  
2D And 3D

Epilepsy is characterized by the presence of recurrent seizures. A seizure can be defined as “an episodic disturbance of movement, feeling, or consciousness caused by sudden synchronous, inappropriate, and excessive electrical discharges in the cerebral cortex”. One in every three patients with epilepsy is probable to be severely disabled. It is continuing this scenario as an attempt to develop potent and nontoxic anti-convulsant agents. Recently the discovery of benzothiazepine derivatives as an anticonvulsant agent is a significant area for research in medicinal chemistry as it is free from all side effects which is shown by a developed as an anticonvulsant agent. In this paper, we have presented results of 2D, and 3D docking poses studies of a series of 300 (Three series) molecules containing 1,5-benzothiazepine pharmacophore as anti-convulsant agents. Docking analysis was utilized to predict the mechanism of action of the designed derivatives for anticonvulsant potential. All the molecules exhibited a binding score in the range of -82.61 to - 118.25 kcal/mol. Most active molecules from Series 1, 2 and 3 exhibited hydrogen bond interactions with LEU282B, LEU282B and LEU282B. Also for the selected standard sodium phenytoin showed the hydrogen bond interaction with LYS637A. It was noted that the docking score of 1a to 10a, 101b to 110b and 201c to 210c was almost the same as that of selected standard sodium phenytoin. The protein showed hydrogen bonding with all synthesized compound showed potential against epilepsy with GABA nergic mechanism.  Keywords: Anti-convulsant; 1,5-benzothiazepine; V-Life MDS 4.3.

scholarly journals Evolving potential vaccine candidates amid COVID-19 pandemic: Pipeline to Lifeline

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 1323-1333
Author(s):  
Anshu Kumar Yadav ◽  
Akila Prashant ◽  
Prashant Vishwanath ◽  
Surinder Singh ◽  
Nirmal Kumar Ganguly
Keyword(s):  
Docking Studies ◽  
Experimental Models ◽  
World Health ◽  
Target Cells ◽  
Vaccine Candidates ◽  
Clinical Phase ◽  
Preclinical Phase ◽  
The World ◽  
Potential Vaccine ◽  
Health Organization

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is globally explored to decode its genomic functionality along with elucidating immunogenic pathways to design and develop an efficient vaccine. Potential immunogenic targets have been screened and validated through preclinical evaluation using experimental models. Computational platform and molecular docking studies are also being conducted to study the immunodynamic mechanisms which involve suitable epitopes of host target cells that respond to the potential vaccine candidate eliciting an immune-mediated reaction. Although SARS-CoV-2 possesses genetic similarities with previously known human coronaviruses, the emergence of novel mutational changes in the immunodominant region of the receptor-binding domain of viral spike protein resulted in high transmissibility and fatality. On a periodical basis, the World Health Organization (WHO) publishes the update on evolving vaccine candidates and encouraging several vaccine developers including multinational companies to join the worldwide campaign against the COVID-19 pandemic. As per the latest WHO landscape draft of evolving vaccine candidates, around 180 teams with respective vaccine candidates across the world are working by utilizing multiple developmental platforms, out of which 35 candidates have entered clinical phase trial and 145 candidates are under the preclinical phase of evaluation. They are also being tested for undesired immunopotentiation without compromising their safety and efficacy. These vaccine candidates along with their advantages and various challenges have been reviewed in this article.

Antituberculosis Screening of Crude Extracts of M.Spicata(Dalz.) Nicolson

2017 ◽  
Vol 9 (6) ◽  
Author(s):  
D. G. Karpe ◽  
S. P. Lawande
Keyword(s):  
Antitubercular Activity ◽  
World Health ◽  
Antituberculosis Activity ◽  
Minimal Inhibition Concentration ◽  
Reference Drug ◽  
Crude Extracts ◽  
Inhibition Concentration ◽  
The World ◽  
Health Organization

World Health Organization reports on Tuberculosis shows that TB is a big problem in the world. More than 23% cases of Tuberculosis found in India amongst global total. Plants are good sources of phytomedicines. Plants contain active constituents and are easily available in nature. The present study was done to evaluate In-vitro antituberculosis activity of crude extracts of m.spicata .We used Minimal Inhibition Concentration (MIC) method to evaluate the antituberculosis activity. Higher concentarations of crude extracts were needed to show antitubercular activity as compared with standard reference drug Isoniazid.

ATP Synthase Inhibitors as Anti-tubercular Agents: QSAR Studies in Novel Substituted Quinolines

2020 ◽  
Vol 20 (29) ◽  
pp. 2723-2734
Author(s):  
Anil K. Saxena ◽  
Muneer Alam
Keyword(s):  
Atp Synthase ◽  
Antitubercular Activity ◽  
Pharmacophore Modeling ◽  
World Health ◽  
Data Set ◽  
Antitubercular Drugs ◽  
Qsar Analysis ◽  
Qsar Studies ◽  
Substituted Quinolines ◽  
Qsar Models

Background: Tuberculosis (TB) is a major infectious disease caused by Mycobacterium Tuberculosis. As per the World Health Organization (WHO) report of 2019, there were 1.5 million deaths in the year 2018, mainly because of multi- and extensively drug-resistant tuberculosis (MDR & XDR-TB). Among several antitubercular drugs in clinical trials, bedaquiline (TMC207) is a highly promising drug that was approved by the FDA in 2012 and marketed in 2016 for the treatment of multidrug resistant TB in combination with other drugs. Bedaquiline acts on mycobacterial ATP synthase and is highly effective in replicating as well as on dormant mycobacteria. Several series of substituted quinolines have been reported with their antitubercular and ATP synthase inhibitory activity. Methods: To understand the role of physicochemical parameters like hydrophobicity, electronic and steric factors in eliciting the biological response, the Quantitative structure-activity relationship (QSAR) studies have been carried out using the computed parameters as independent variable and activity (-log IC50/MIC) as the dependent variable. Results: The developed QSAR models in terms of positively contributing Molar Refractivity (MR) and negatively contributing Partition Coefficient (PC) and Connolly Molecular Area (CMA) parameters have high predictivity as also shown on external data set and the mean value of the computed 3D parameters of enantiomers may be used in QSAR analysis for racemic compounds. Conclusion: These results are also substantiated by pharmacophore modeling. The similar dependence of antitubercular activity against whole-cell M.Tb.H37Rv on MR and CMA suggests ATP synthase as the main target for antitubercular activity and the QSAR models may be useful in the identification of novel antitubercular agents.

scholarly journals Catalytic and Molecular Properties of Rabbit Liver Carboxylesterase Acting on 1,8-Cineole Derivatives

2012 ◽  
Vol 7 (9) ◽  
pp. 1934578X1200700
Author(s):  
María del H. Loandos ◽  
Ana C. Muro ◽  
Margarita B. Villecco ◽  
Marcelo F. Masman ◽  
Paul G.M. Luiten ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Molecular Modeling ◽  
Molecular Properties ◽  
Rabbit Liver ◽  
Enantioselective Hydrolysis ◽  
Docking Simulations ◽  
Hydrogen Bond Interactions ◽  
Molecular Dynamics Calculations ◽  
Hydrolysis Of

Rabbit liver carboxylesterase (rCE) was evaluated as the catalyst for the enantioselective hydrolysis of (±)-3-endo-acetyloxy-1,8-cineole [(±)-4], which yields (1S,3S,4R)-(+)-3-acetyloxy-1,8-cineole [(+)-4] and (1R,3R,4S)-(-)-3-hydroxy-1,8-cineole [(-)-3]. Enantioselective asymmetrization of meso-3,5-diacetoxy-1,8-cineol (5) gives (1S,3S,4R,5R)-(-)-3-acetyloxy-5-hydroxy-1,8-cineole (6), with high enantioselectivity. rCE has been chosen to perform both experiments and molecular modeling simulations. Docking simulations combined with molecular dynamics calculations were used to study rCE-catalyzed enantioselective hydrolysis of cineol derivatives. Both compounds were found to bind with their acetyl groups stabilized by hydrogen bond interactions between their oxygen atoms and Ser221.

Molecular Docking Studies of Indolyl-Benzodioxyl-Chalcone, Pyrrolyl-Benzodioxyl- Chalcone, and Thiophenyl-Benzodioxyl-Chalcone as an Antimalarial Agent

2021 ◽  
Vol 874 ◽  
pp. 136-142
Author(s):  
Kamilia Mustikasari ◽  
Joshua Eka Harap ◽  
Tanto Budi Susilo ◽  
Noer Komari
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Docking Studies ◽  
Kcal Mole ◽  
Docking Simulations ◽  
Drug Candidates ◽  
Hydrogen Bond Interactions ◽  
New Compounds ◽  
Native Ligand

The drug resistance condition of P. falciparum pose a major challenge in the fight against malaria. This prompts a comprehensive research in an effort to discover new drug candidates. Therefore, chalcone was modified into 24 new compounds, including indolyl-benzodioxyl-chalcone, pyrrolyl-benzodioxyl-chalcone, and thiophenyl-benzodioxyl-chalcone in the course of this study. Moreover, these compounds are commercial malaria mediciations screened for their inhibitory activity using molecular docking simulations. Subsequent results of combined indolyl-benzodioxyl-chalcone and PfDHFR-TS showed the intrinsic indolyl components produced stronger interactions referenced to pyrrolyl-benzodioxyl-chalcone, thiophenyl-benzodioxyl-chalcone, and chloroguanide. Under these circumstances, intense PfDHFR-TS-indolyl-benzodioxyl-chalcone complex was produced with lower binding affinity values (-7.32 to -8.43 kcal/mole) referenced to PfDHFR-TS-pyrrolyl-benzodioxyl-chalcone (-6.38 to -6.68 kcal/mole), PfDHFR-TS-Thiophenyl-benzodioxyl-chalcone (-6.47 to -6.52 kcal/mole), and PfDHFR-TS-chloroguanide (-6.75 kcal/mole). Furthermore, the hydrogen bond interactions developed by indolyl-benzodioxyl-chalcone (7-10) are observably similar to standard chloroguanide compounds and WR99210. These compounds also possess a binding affinity similar to WR99210 (native ligand) and are expected to be potentially anti-malarial candidates.

scholarly journals Molecular docking analysis of stevioside with AKT and PPARγ

2021 ◽  
Vol 17 (1) ◽  
pp. 283-288
Author(s):  
Abilasha Deenadayalan ◽  
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Docking Studies ◽  
Autodock Vina ◽  
Docking Analysis ◽  
Hydrogen Bond Interactions ◽  
Ppar Γ ◽  
Molecular Docking Analysis

Stevioside is a diterpenoid glycoside consisting of an aglycone (steviol) and three glucose molecules. It is commonly used as an anti-hyperglycemic food because of its non-caloric property. Therefore, it is of interest to document the interactions of stevioside with AKT & PPAR-γ proteins using Autodock Vina PyRx docking techniques. Results of the docking studies indicate that stevioside had more than two hydrogen bond interactions with the AKT and PPAR γ protein for further consideration.

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