scholarly journals Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Baki Vijaya Bhaskar ◽  
Aluru Rammohan ◽  
Tirumalasetty Munichandra Babu ◽  
Gui Yu Zheng ◽  
Weibin Chen ◽  
...  
Keyword(s):  
Binding Energy ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Binding Pocket ◽  
Pharmacophore Modeling ◽  
Boswellic Acid ◽  
Lead Compounds ◽  
Donor And Acceptor ◽  
In Silico Studies ◽  
Dietary Agents

AbstractDietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, β-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from − 11.5 to − 8.5 kcal mol−1. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan
Keyword(s):  
Side Effects ◽  
Medicinal Plants ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Psidium Guajava ◽  
Current Status ◽  
Future Perspective ◽  
Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

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

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.

Design, Synthesis, In Vitro and In Silico Studies of Some Novel Triazoles as Anticancer Agents for Breast Cancer

2021 ◽  
pp. 131198
Author(s):  
Derya Osmaniye ◽  
Begum Nurpelin Saglik ◽  
Serkan Levent ◽  
Sinem Ilgın ◽  
Yusuf Ozkay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Anticancer Agents ◽  
In Silico ◽  
Design Synthesis ◽  
In Silico Studies

scholarly journals Pharmacological Characterisation of Pseudocerastes and Eristicophis Viper Venoms Reveal Anticancer (Melanoma) Properties and a Potentially Novel Mode of Fibrinogenolysis

2021 ◽  
Vol 22 (13) ◽  
pp. 6896
Author(s):  
Bianca op den Brouw ◽  
Parviz Ghezellou ◽  
Nicholas R. Casewell ◽  
Syed Abid Ali ◽  
Behzad Fathinia ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Serine Proteases ◽  
Human Melanoma ◽  
Snake Venoms ◽  
Lead Compounds ◽  
Bioactive Properties ◽  
Fibrinogenolytic Activity ◽  
Pharmacological Potential ◽  
Hydrolysis Of ◽  
Viper Venoms

Venoms are a rich source of potential lead compounds for drug discovery, and descriptive studies of venom form the first phase of the biodiscovery process. In this study, we investigated the pharmacological potential of crude Pseudocerastes and Eristicophis snake venoms in haematological disorders and cancer treatment. We assessed their antithrombotic potential using fibrinogen thromboelastography, fibrinogen gels with and without protease inhibitors, and colourimetric fibrinolysis assays. These assays indicated that the anticoagulant properties of the venoms are likely induced by the hydrolysis of phospholipids and by selective fibrinogenolysis. Furthermore, while most fibrinogenolysis occurred by the direct activity of snake venom metalloproteases and serine proteases, modest evidence indicated that fibrinogenolytic activity may also be mediated by selective venom phospholipases and an inhibitory venom-derived serine protease. We also found that the Pseudocerastes venoms significantly reduced the viability of human melanoma (MM96L) cells by more than 80%, while it had almost no effect on the healthy neonatal foreskin fibroblasts (NFF) as determined by viability assays. The bioactive properties of these venoms suggest that they contain a number of toxins suitable for downstream pharmacological development as candidates for antithrombotic or anticancer agents.

GR-mediated anti-inflammation of α-boswellic acid: Insights from in vitro and in silico studies

2021 ◽  
Vol 155 ◽  
pp. 112379
Author(s):  
Jie Zhang ◽  
Jiarui Zhao ◽  
Yantong Sun ◽  
Yuan Liang ◽  
Jingqi Zhao ◽  
...  
Keyword(s):  
In Silico ◽  
Boswellic Acid ◽  
In Silico Studies ◽  
Anti Inflammation

scholarly journals Mammalian deubiquitinating enzyme inhibitors display in vitro and in vivo activity against malaria parasites and potentiate artemisinin action

2020 ◽  
Author(s):  
Nelson V. Simwela ◽  
Katie R. Hughes ◽  
Michael T. Rennie ◽  
Michael P. Barrett ◽  
Andrew P. Waters
Keyword(s):  
Anticancer Agents ◽  
Drug Targets ◽  
Reverse Genetics ◽  
Enzyme Inhibitors ◽  
Artemisinin Resistance ◽  
Drug Repurposing ◽  
Antimalarial Drugs ◽  
Malaria Parasites

AbstractCurrent malaria control efforts rely significantly on artemisinin combinational therapies which have played massive roles in alleviating the global burden of the disease. Emergence of resistance to artemisinins is therefore, not just alarming but requires immediate intervention points such as development of new antimalarial drugs or improvement of the current drugs through adjuvant or combination therapies. Artemisinin resistance is primarily conferred by Kelch13 propeller mutations which are phenotypically characterised by generalised growth quiescence, altered haemoglobin trafficking and downstream enhanced activity of the parasite stress pathways through the ubiquitin proteasome system (UPS). Previous work on artemisinin resistance selection in a rodent model of malaria, which we and others have recently validated using reverse genetics, has also shown that mutations in deubiquitinating enzymes, DUBs (upstream UPS component) modulates susceptibility of malaria parasites to both artemisinin and chloroquine. The UPS or upstream protein trafficking pathways have, therefore, been proposed to be not just potential drug targets, but also possible intervention points to overcome artemisinin resistance. Here we report the activity of small molecule inhibitors targeting mammalian DUBs in malaria parasites. We show that generic DUB inhibitors can block intraerythrocytic development of malaria parasites in vitro and possess antiparasitic activity in vivo and can be used in combination with additive effect. We also show that inhibition of these upstream components of the UPS can potentiate the activity of artemisinin in vitro as well as in vivo to the extent that ART resistance can be overcome. Combinations of DUB inhibitors anticipated to target different DUB activities and downstream 20s proteasome inhibitors are even more effective at improving the potency of artemisinins than either inhibitors alone providing proof that targeting multiple UPS activities simultaneously could be an attractive approach to overcoming artemisinin resistance. These data further validate the parasite UPS as a target to both enhance artemisinin action and potentially overcome resistance. Lastly, we confirm that DUB inhibitors can be developed into in vivo antimalarial drugs with promise for activity against all of human malaria and could thus further exploit their current pursuit as anticancer agents in rapid drug repurposing programs.Graphical abstract

scholarly journals Pharmacophore modeling, virtual computational screening and biological evaluation studies

2017 ◽  
Author(s):  
Serena Dotolo ◽  
Angelo Facchiano
Keyword(s):  
Molecular Mechanisms ◽  
Prediction Models ◽  
Pharmacophore Modeling ◽  
Biological Evaluation ◽  
Bioactive Molecules ◽  
Investigational Drug ◽  
Discovery Studio ◽  
Lead Compounds ◽  
Computational Screening ◽  
Computational Strategy

Drug discovery process plays an important role in identifying new investigational drug-likes and developing new potential inhibitors related to a determinate target, in biopharmaceutical field [1]. An alternative promising and efficient used to identify new active substances is Pharmacophore modeling method.We defined a new computational strategy protocol characterized by the use of bioinformatics online tools and by the application of locally installed tools, for lead candidates generation-optimization able to reduce the cycle time and cost of this process and to promote the next steps of study [2].Hence, we have tried to apply this new computational procedure, in a more detailed screening, of small bioactive molecules, searching and identifying new candidates as “lead compounds”, potentially able to inhibit biological target AKT1 human protein and its related molecular mechanisms [3].The workflow executed in our work has been characterized by a multi-step design, which concerns different topics: search in PDB database of a model structure for AKT1, pharmacophore modeling and virtual computational screening, biological evaluation divided in two parts (molecular validation of selected compounds and study of physical-chemical properties related to pharmacokinetic/pharmacodynamics prediction models). All these step have been performed through PHARMIT (http://pharmit.csb.pitt.edu) and Discovery Studio 4.5 platform.We selected the PDB structure 3O96 as the reference complex (protein-ligand), and we analyzed it by means of PHARMIT and Discovery Studio, to generate four different “pharmacophore models” with four different list of natural compounds.It is performed a thorough screening of compounds applying several filters, to find some good candidates as possible natural AKT1 allosteric inhibitors.The compounds that match a well-defined pharmacophore have been analyzed through direct molecular docking, for selecting only the best candidates and studying the protein-ligand interactions. Selected compounds have been investigated in more details, to trace their origin, by their chemical-physical properties.This information can help us to predict some plausible enzyme-catalyzed reaction pathways, through PathPred web-server and KEGG compound database, in order to highlight the most important reactions for biosynthesis of compounds and obtain PharmacoKinetics/PharmacoDynamics (PK/PD) models, to investigate the ADMET properties of these lead compounds and to study their behavior in some biological systems, for the next experimental assays.This new computational strategy has been very efficient in showing what could be good “lead compounds” and potential natural inhibitors of AKT1 and PI3K/AKT1 signaling cascade. Therefore, the next steps could be the experimental analysis of pharmacokinetics-pharmacodynamics and toxicity properties “in vitro/in vivo”, in order to evaluate the results obtained “in silico”.

scholarly journals Nature Potential for COVID-19: Targeting SARS-CoV-2 Mpro Inhibitor with Bioactive Compound

2021 ◽  
Author(s):  
Kaushik Kumar Bharadwaj ◽  
Tanmay Sarkar ◽  
Arabinda Ghosh ◽  
Debabrat Baishya ◽  
Bijuli Rabha ◽  
...  
Keyword(s):  
Binding Energy ◽  
Antiviral Activity ◽  
Binding Free Energy ◽  
Bioactive Compound ◽  
Binding Pocket ◽  
Stable Conformation ◽  
Lipinski’S Rule ◽  
Macrolactin A

<p>Corona viruses were first identified in 1931 and SARS-CoV-2 is the most recent. COVID-19 is a pandemic that put most of the world on lockdown and the search for therapeutic drugs is still on-going. Therefore, this study uses <i>in silico</i> screening to identify natural bioactive compounds from fruits, herbaceous plants and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2(PDB: 6LU7). We have used various screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME (absorption, distribution, metabolism, and excretion), molecular dynamics (MD) simulation and MM/GBSA (molecular mechanics/generalized born and surface area continuum solvation). 17 compounds were shortlisted using Lipinski’s rule. 5 compounds revealed significantly good predicted antiviral activity values and out of them only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy values of -9.22 and -8.00 kcal/mol within the binding pocket, catalytic residues (HIS 41 and CYS 145) of M<sup>pro</sup>. These two compounds were further analyzed for their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective as therapeutic agents for developing drugs for clinical trials. MD simulations showed that protein-ligand complexes of Macrolactin A and Stachyflin were stable for 100 nano seconds. The MM/GBSA calculations of M<sup>pro</sup> – Macrolactin A complex indicated higher binding free energy (-42.58 ± 6.35 kcal/mol) with M<sup>pro </sup>protein target receptor (6LU7). DCCM and PCA analysis on the residual movement in the MD trajectories confirmed the good stability on Macrolactin A bound state of 6LU7. This signify the stable conformation of 6LU7 with high binding energy with Macrolactin A. Thus, this study showed that Macrolactin A could be an effective therapeutical agent for SARS-CoV-2protease (6LU7) inhibition. Additional <i>in vitro </i>and<i> in vivo </i>validations are needed to determine efficacy and dose of Macrolactin A in biological systems.</p>

scholarly journals Inhibition of Phosphodiesterase 5 Enzyme by Pterine- 6 Carboxylic Acid from Baphia nitida –Related to Erectile Dysfunction: Computational Kinetic

2020 ◽  
pp. 49-55
Author(s):  
Wopara, Iheanyichukwu ◽  
S. K. Mobisson ◽  
Egelege Aziemeola Pius ◽  
A. A. Uwakwe ◽  
M. O. Wegwu
Keyword(s):  
Erectile Dysfunction ◽  
Carboxylic Acid ◽  
Active Site ◽  
In Silico ◽  
Binding Pocket ◽  
Docking Studies ◽  
Drug Candidate ◽  
In Silico Docking ◽  
In Silico Studies ◽  
Phosphodiesterase 5

Treatment of erectile dysfunction is associated with inhibition of Phosphodiesterase 5 enzyme. This study deals with the evaluation of Pterin-6-carboxylic acid inhibitory activity on phosphodiesterase 5 (PDB ID: 4OEW) using in silico docking studies. Pterin-6-carboxylic acid from Baphia nitida was isolated using GC-MS and docked into PDE5 active site. The docking result showed that pterin-6-carboxylic acid bind to the active site of phosphodiesterase 5 with the binding energy value of -7.1 and 2.05A° - 2.23A° when compared with other compound found in the plant. Moreso, docking analysis with the ligand identified specific residues such as: Ile 778, Phe 820, Gln 817, Ser 815 and Gln 775 within the binding pocket which played an important role in the ligand binding affinity to the protein. Result from our In silico studies hypothesized that pterin-6-carboxylic acid can be an inhibitory agent for PDE5 protein which could be a potential drug candidate for the treatment of erectile dysfunction.

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