Editor’s Choice – Integrated Computational Analysis on Some Indolo-quinoline Derivatives for the Development of Novel Antiplasmodium Agents: CoMFA, Pharmacophore Mapping, Molecular Docking and ADMET Studies

Author(s):Chaitali MallickMitali MishraVivek AsatiVarsha KashawRatnesh DasArun K. Iyer and Sushil Kumar Kashaw*

Volume 17, Issue 1, 2022

Published on: 06 September, 2021

Article ID: e011221196199

Pages: 47

DOI: 10.2174/1574362416666210906155929


Background: The development of multi-resistant strains of the Plasmodium parasite has become a global problem. Therefore, designing of new antimalarial agents is an exclusive solution.

Objective: To improve the activity and identify potentially efficacious new antimalarial agents, integrated computational perspectives such as pharmacophore mapping, 3D-QSAR and docking study have been applied to a series of indolo-quinoline derivatives.

Methods: The pharmacophore mapping generated various hypotheses based on key functional features and the best hypothesis ADRRR_1 revealed that indolo-quinoline scaffold is essential for antimalarial activity. 3D-QSAR model was established based on CoMFA and CoMSIA models by using 30 indoloquinoline analogues as training set and the rest of 19 as test set.

Results: The molecular field analysis (MFA) with PLS (partial least-squares) method was used to develop significant CoMFA (q2=0.756, r2=0.996) and CoMSIA (q2=0.703, r2=0.812) models. The CoMFA and CoMSIA models showed good predictive ability with r2 pred values of 0.9623 and 0.9214, respectively. Docking studies were performed by using pfLDH to identify structural insight into the active site and results signify that the quinoline nitrogen acts as a hydrogen bond acceptor region to facilitate interaction with Glu122. Finally, designed molecules were screened through the ADMET tool to evaluate the pharmacokinetic and drug-likeness parameters.

Conclusion: Thus, these studies suggested that established models have good predictability and would help in the optimization of newly designed molecules that may produce potent antimalarial activity. Read now: https://bit.ly/3LqNLZv

Kudos Article – Discovery of natural anti-cancerous therapeutic molecules that target topoisomerases

Swati Singh, Veda P. Pandey, Kusum Yadav, Anurag Yadav, U. N. Dwivedi

DOI: 10.2174/1389203721666200918152511

What is it about?

Thus, the present review describes the anticancer potential of plant-derived secondary metabolites belonging to alkaloids, flavonoids and terpenoids directed against topoisomerases. Furthermore, in view of the recent advances made in the field of computer-aided drug design, the present review also discusses the use of computational approaches such as ADMET, molecular docking, molecular dynamics simulation and QSAR to assess and predict the safety, efficacy, potency and identification of these potent anti-cancerous therapeutic molecules.

Why is it important?

Cancer is the second leading cause of global deaths of millions of people. Some of the bottlenecks in the successful development of anticancer drugs include the absence of cancer specificity, toxicity and the development of multi-drug resistance among cancerous cells. Since ancient times, plant-derived products are being used as therapeutic agents against several diseases. The development of cancer prevention and healthcare products from natural products has a broader prospect, greater economic and social benefits compared with prevalent synthetic anticancerous drugs. Read now: https://bit.ly/3qvkwv3

Most Cited Article – Molecular Docking and Dynamics Simulation Studies of a Dataset of NLRP3 Inflammasome Inhibitors

Author(s):Igor J. dos Santos Nascimento*Thiago M. de Aquino and Edeildo F. da Silva-Júnior

Volume 15, Issue 2, 2021

Published on: 26 January, 2022

Page: [80 – 86]

Pages: 7

DOI: 10.2174/2772270816666220126103909


Background: The organism’s defense against aggressive agents is performed by the innate immune system via activation of pattern-recognition receptors (PRRs). Initially, these agents are recognized by the immune system, resulting in the inflammatory response that activates the pathogen elimination and tissue repair. Inflammasomes are macromolecules related to the host’s response to endo or exogenous aggressive agents. Thus, inflammation mediated by inflammasomes plays an important role in the pathogenesis of diseases, such as neurodegenerative disorders, autoimmune diseases, and type 2 diabetes, justifying their attractiveness as drug targets. One of the most important tasks remains in the ATPase nucleotide-binding oligomerization domain nucleotide- binding domain leucine-rich repeat-containing receptors protein 3 (NLRP3), in which the blocking of its oligomerization is related to the functional inhibition of inflammasomes. Here, we performed molecular docking and dynamics simulations for NP3-146, an analog of MCC950, to obtain information about the complex stability and main interactions with amino acid residues from NLRP3.

Methods: By using the crystalized structure recently deposited in the protein data bank (7alv), molecular docking in GOLD software and molecular dynamics simulations in GROMACS software were performed to generate the RMSD RMSF, Rg, SASA, and H-bond plots.

Results: The results of RMSD, RMSF, Rg, SASA, and H-bond plots of both complexes confirmed the stability at the active site. Besides, the analyses of the most stable conformation showed that the main interactions are performed with Ala227, Ala228, Pro352, Ile411, Phe575, and Arg578 residues.

Conclusion: This report confirmed the stability of NP3-146, similar to the known inhibitor MCC950, providing useful information for designing NLRP3 inhibitors. Read now: https://bit.ly/3uYyHvb

Testimonial By Ratish Mishra

Read what our Authors have to say about publishing in our Journal

Ratish Mishra

Journal Name: Current Enzyme Inhibition

Contributed Article: Exploring Molecular Docking Studies Of Alanine Racemase Inhibitors From Elettaria Cardamomum

Open Access Articles | An Integrated Computational Approach for Plant-Based Protein Tyrosine Phosphatase Non-Receptor Type 1 Inhibitors


Journal Name: Current Computer-Aided Drug Design

Author(s): Shabana Bibi, Katsumi Sakata*.



Graphical Abstract:



Background: Protein tyrosine phosphatase non-receptor type 1 is a therapeutic target for the type 2 diabetes mellitus. According to the International Diabetes Federation 2015 report, one out of 11 adults suffers from diabetes mellitus globally.

Objective: Current anti-diabetic drugs can cause life-threatening side-effects. The present study proposes a pipeline for the development of effective and plant-derived anti-diabetic drugs that may be safer and better tolerated.

Methods: Plant-derived protein tyrosine phosphatase non-receptor type 1 inhibitors possessing antidiabetic activity less than 10µM were used as a training set. A common feature pharmacophore model was generated. Pharmacophore-based screening of plant-derived compounds of the ZINC database was conducted using ZINCpharmer. Screened hits were assessed to evaluate their drug-likeness, pharmacokinetics, detailed binding behavior, and aggregator possibility based on their physiochemical properties and chemical similarity with reported aggregators.

Results: Through virtual screening and in silico pharmacology protocol isosilybin (ZINC30731533) was identified as a lead compound with optimal properties. This compound can be recommended for laboratory tests and further analyses to confirm its activity as protein tyrosine phosphatase nonreceptor type 1 inhibitor.

Conclusion: The present study has identified plant-derived anti-diabetic virtual lead compound with the potential to inhibit protein tyrosine phosphatase non-receptor type 1, which may be helpful to enhance insulin production. This computer-aided study could facilitate the development of novel pharmacological inhibitors for diabetes treatment. To read out more, please visit: http://www.eurekaselect.com/151386/article

Podcast | In Silico Appraisal, Synthesis, Antibacterial Screening and DNA Cleavage for 1,2,5-thiadiazole Derivative

Author(s): Suraj N. Mali*, Sudhir Sawant, Hemchandra K. Chaudhari*, Mustapha C. Mandewale


Graphical Abstract:



Background: Thiadiazole not only acts as “hydrogen binding domain” and “two-electron donor system” but also as constrained pharmacophore.

Methods: The maleate salt of 2-((2-hydroxy-3-((4-morpholino-1, 2,5-thiadiazol-3-yl) oxy) propyl) amino)- 2-methylpropan-1-ol (TML-Hydroxy)(4) has been synthesized. This methodology involves preparation of 4-morpholino-1, 2,5-thiadiazol-3-ol by hydroxylation of 4-(4-chloro-1, 2,5-thiadiazol-3-yl) morpholine followed by condensation with 2-(chloromethyl) oxirane to afford 4-(4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol- 3-yl) morpholine. Oxirane ring of this compound was opened by treating with 2-amino-2-methyl propan-1- ol to afford the target compound TML-Hydroxy. Structures of the synthesized compounds have been elucidated by NMR, MASS, FTIR spectroscopy.

Results: The DSC study clearly showed that the compound 4-maleate salt is crystalline in nature. In vitro antibacterial inhibition and little potential for DNA cleavage of the compound 4 were explored. We extended our study to explore the inhibition mechanism by conducting molecular docking, ADMET and molecular dynamics analysis by using Schrödinger. The molecular docking for compound 4 showed better interactions with target 3IVX with docking score of -8.508 kcal/mol with respect to standard ciprofloxacin (docking score= -3.879 kcal/mol). TML-Hydroxy was obtained in silico as non-carcinogenic and non-AMES toxic with good percent human oral absorption profile (69.639%). TML-Hydroxy showed the moderate inhibition against Mycobacteria tuberculosis with MIC 25.00 μg/mL as well as moderate inhibition against S. aureus, Bacillus sps, K. Pneumoniae and E. coli species.

Conclusion: In view of the importance of the 1,2,5-thiadiazole moiety involved, this study would pave the way for future development of more effective analogs for applications in medicinal field. For article details, please visit: http://www.eurekaselect.com/169670/article


Editors Choice Article | Rational Design of Colchicine Derivatives as anti-HIV Agents via QSAR and Molecular Docking

Journal Name: Medicinal Chemistry

Author(s): Apilak Worachartcheewan*, Napat Songtawee, Suphakit Siriwong, Supaluk Prachayasittikul*, Chanin Nantasenamat, Virapong Prachayasittikul.



Background: Human immunodeficiency virus (HIV) is an infective agent that causes an acquired immunodeficiency syndrome (AIDS). Therefore, the rational design of inhibitors for preventing the progression of the disease is required.

Objective: This study aims to construct quantitative structure-activity relationship (QSAR) models, molecular docking and newly rational design of colchicine and derivatives with anti-HIV activity.

Methods: A data set of 24 colchicine and derivatives with anti-HIV activity were employed to develop the QSAR models using machine learning methods (e.g. multiple linear regression (MLR), artificial neural network (ANN) and support vector machine (SVM)), and to study a molecular docking.

Results: The significant descriptors relating to the anti-HIV activity included JGI2, Mor24u, Gm and R8p+ descriptors. The predictive performance of the models gave acceptable statistical qualities as observed by correlation coefficient (Q2) and root mean square error (RMSE) of leave-one out cross-validation (LOO-CV) and external sets. Particularly, the ANN method outperformed MLR and SVM methods that displayed LOO−CV 2 Q and RMSELOO-CV of 0.7548 and 0.5735 for LOOCV set, and Ext 2 Q of 0.8553 and RMSEExt of 0.6999 for external validation. In addition, the molecular docking of virus-entry molecule (gp120 envelope glycoprotein) revealed the key interacting residues of the protein (cellular receptor, CD4) and the site-moiety preferences of colchicine derivatives as HIV entry inhibitors for binding to HIV structure. Furthermore, newly rational design of colchicine derivatives using informative QSAR and molecular docking was proposed.

Conclusion: These findings serve as a guideline for the rational drug design as well as potential development of novel anti-HIV agents. To read out more, please visit: http://www.eurekaselect.com/165617/article

Editor’s Choice Article | Design, Microwave Assisted Organic Synthesis and Molecular Docking Studies of Some 4 – (3H)-Quinazolinone Derivatives as Inhibitors of Colchicine- Binding Site of Tubulin

Author(s): Rakesh D. Amrutkar*, Mahendra S. Ranawat.


Currently, new chemical entities developed as anticancer agents against tubulin as a protein target. The present work, a quinazoline derivatives were used to design and synthesized by microwave irradiation as an anticancer agent through selective inhibitors of colchicinebinding site of tubulin by the molecular docking of quinazoline derivatives using Schrödinger, LLC, New York, NY, 2017. Read out full article here: http://www.eurekaselect.com/166586/article



ARTICLE BY DISEASE – Docking and Molecular Dynamics Study on the Inhibitory Activity of Novel Inhibitors on Epidermal Growth Factor Receptor (EGFR)





EGFR is the cell-surface receptor. Its overexpression or overactivity has been associated with a number of cancers, including breast, lung, ovarian, and anal cancers. Many therapeutic approaches are aimed at the EGFR. A series of 2, 7-diamino-thiazolo [4,5-d] pyrimidine analogues are among the most highly potent and selective inhibitors of EGFR described to date. For in-depth investigation into the structural and chemical features responsible for the binding recognition mechanism concerned, as well as for exploring the binding pocket of these compounds, we performed a series of automated molecular docking operations. It was revealed that the binding site consisted of three main areas (P1, P2 and P3) composed of most of the hydrophobic amino acids able to accommodate the lipophilic arms of the compounds investigated. However, the solvent interface did not make much contribution to the binding of the inhibitors. The presence of residues Met793 and Asp855 may also be responsible for the binding recognition through H-bond interactions, with Phe856 through a T-shape π-π stacking interaction. The interaction model and pharmacophore of EGFR inhibitors were derived that can be successfully used to explain the different biologic activities of these inhibitors. Moreover, the docking results were quite robust as further validated by molecular dynamics. It is anticipated that the findings reported here may provide very useful information or clue for designing effective drugs for the therapeutic treatment of EGFR-related cancer.


For more details, please visit: http://www.eurekaselect.com/node/87265/article

EDITOR’S CHOICE ARTICLE – Parallelization of Molecular Docking: A Review

Journal Name: Current Topics in Medicinal Chemistry

Author(s): Dong Dong, Zhijian Xu, Wu Zhong, Shaoliang Peng*.



Graphical Abstract:



Molecular docking, as one of the widely used virtual screening methods, aims to predict the binding-conformations of small molecule ligands to the appropriate target binding site. Because of the computational complexity and the arrival of the big data era, molecular docking requests High- Performance Computing (HPC) to improve its performance and accuracy. We discuss, in detail, the advances in accelerating molecular docking software in parallel, based on the different common HPC platforms, respectively. Not only the existing suitable programs have been optimized and ported to HPC platforms, but also many novel parallel algorithms have been designed and implemented. This review focuses on the techniques and methods adopted in paralyzing docking software. Where appropriate, we refer readers to exemplary case studies.



For more details, please visit: http://www.eurekaselect.com/164852/article 

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