In silico Analysis and Molecular Docking Studies of Novel 4-Amino-3- (Isoquinolin-4-yl)-1H-Pyrazolo[3,4-d]Pyrimidine Derivatives as Dual PI3-K/mTOR Inhibitors

2019 ◽  
Vol 16 (3) ◽  
pp. 297-306
Author(s):  
Ishan I. Panchal ◽  
Sandip N. Badeliya ◽  
Rakesh Patel ◽  
Ashish Patel ◽  
Animesh Devaligar
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
In Silico ◽  
Growth Control ◽  
In Silico Analysis ◽  
Software Tool ◽  
Mtor Inhibitors ◽  
Docking Studies ◽  
Tissue Growth ◽  
Nucleotide Synthesis

Background: mTORC1/ PI3K control multiple anabolic pathways, including protein synthesis, ribosome production, lipogenesis, and nucleotide synthesis, are all important for cell and tissue growth. Sapanisertib and Dactolisib inhibit PI3K/AKT/mTOR pathway, an important signaling pathway for many cellular functions such as growth control, metabolism and translation initiation. Methods: Dactolisib contains quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin scaffold and Sapanisertib contains benzo[d]oxazol-5-yl-1-ethyl-1H-pyrazolo[3,4-d]pyrimidinnucleous. From the reference to both of drug novel series of 4-Amino-3-(isoquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin was developed by molecular docking. In sillico analysis was done with SWISSADME online tools. Results: Among all the designed derivatives, compounds 6(-10.6 kcal/mol) , 12( -10.7 kcal/mol), 14( -10.2 kcal/mol), and 16(-10.2 kcal/mol) have a good binding affinity than others. Biological activity was predicted by Molinspirationonline software tool showing that all compounds are active on G- protein coupled receptor. In silico toxicity profile of designed compounds was performed using the SWISSADME program, indicating that all the compounds follow the Lipinski rule of five and do not penetrate Blood brain barrier. Conclusion: Series of pyrazolo[3,4-d]pyrimidin derivatives gives good binding affinity with pan- PI3-Kinese/Mtor inhibitors. The present study provided a better understanding of the molecular modeling requisite for maintaining and/or improving PI3K/mTOR inhibitors.

Prediction Mechanism of Nevadensin as Antibacterial Agent against S. sanguinis: In vitro and In silico Studies

2021 ◽  
Vol 24 ◽  
Author(s):  
Aldina Amalia Nur Shadrina ◽  
Yetty Herdiyati ◽  
Ika Wiani ◽  
Mieke Hemiawati Satari ◽  
Dikdik Kurnia
Keyword(s):  
Antibacterial Activity ◽  
Molecular Docking ◽  
Dental Caries ◽  
Binding Affinity ◽  
In Silico ◽  
Antibacterial Agent ◽  
In Silico Analysis ◽  
Dna Gyrase ◽  
Silico Analysis

Background: Streptococcus sanguinis can contribute to tooth demineralization, which can lead to dental caries. Antibiotics used indefinitely to treat dental caries can lead to bacterial resistance. Discovering new antibacterial agents from natural products like Ocimum basilicum will help combat antibiotic resistance. In silico analysis (molecular docking) can help determine the lead compound by studying the molecular interaction between the drug and the target receptor (MurA enzyme and DNA gyrase). It is a potential candidate for antibacterial drug development. Objective: The research objective is to isolate the secondary metabolite of O. basilicum extract that has activity against S. sanguinis through in vitro and in silico analysis. Methods: n-Hexane extract of O. basilicum was purified by combining column chromatography with bioactivity-guided. The in vitro antibacterial activity against S. sanguinis was determined using the disc diffusion and microdilution method, while molecular docking simulation of nevadensin (1) with MurA enzyme and DNA gyrase was performed used PyRx 0.8 program. Results: Nevadensin from O. basilicum was successfully isolated and characterized by spectroscopic methods. This compound showed antibacterial activity against S. sanguinis with MIC and MBC values of 3750 and 15000 μg/mL, respectively. In silico analysis showed that the binding affinity to MurA was -8.5 Kcal/mol, and the binding affinity to DNA gyrase was -6.7 Kcal/mol. The binding of nevadensin-MurA is greater than fosfomycin-MurA. Otherwise, Nevadensin-DNA gyrase has a weaker binding affinity than fluoroquinolone-DNA gyrase and chlorhexidine-DNA gyrase. Conclusion: Nevadensin showed potential as a new natural antibacterial agent by inhibiting the MurA enzyme rather than DNA gyrase.

scholarly journals Design, Molecular Docking And In Silico Analysis Of Analogues Of Chloroquine And Hydroxychloroquine Against SARs-COV-2 Target (6w63.pdb)

2020 ◽  
Author(s):  
Naruka Solomon Yakubu ◽  
Olanike Catherine Poyi ◽  
Ezikiel Olabisi Afolabi
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Target Prediction ◽  
In Silico Analysis ◽  
Docking Studies ◽  
Biologically Active ◽  
Dynamic Simulations ◽  
Comparable Activity ◽  
Silico Analysis

Abstract Computer-aided drug design has been an effective strategy and approach to discover, develop, analyze, accelerate and economize design and development of drugs and biologically active molecules. A total of twelve analogues of chloroquine (CQ) and hydroxychloroquine (HCQ) were designed and virtually analyzed using PyRx software, Molinspiration, Swiss ADME, Swiss-Target Prediction software and ProTox-II-Prediction of toxicity platform. Based on the docking studies carried out using Autodock vina, five analogues; H-368 (-6.0 Kcal/mol), H-372 (--6.0 Kcal/mol), H-156 (-5.9 Kcal/mol), H-139 (-5.7 Kcal/mol), C-136 (-5.7 Kcal/mol) exhibited higher binding affinity compared to HCQ(-5.5 Kcal/mol), while all twelve analogues exhibited higher binding affinity compared to CQ (-4.5Kcal/mol). In silico analysis of toxicity profile of this analogues shows a lower potential to toxicity and a comparable activity on some major isoforms of cytochrome P450. But unlike the parent molecules, both H-139 and H-156 are substrates of P-glycoproteins (P-gp) which implies that these analogues possess high clearance and less pharmacokinetic-related drug-drug interactions compared to the parent molecules. Herein we propose these analogues as potential inhibitors or lead compounds against the coronavirus with a view of conducting more molecular dynamic simulations, synthesizing and conducting in vitro studies on them.

scholarly journals Molecular Docking Studies of a Cyclic Octapeptide-Cyclosaplin from Sandalwood

2019 ◽  
Author(s):  
Abheepsa Mishra ◽  
Satyahari Dey
Keyword(s):  
Molecular Docking ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Binding Affinity ◽  
In Silico ◽  
Docking Studies ◽  
Screening Methods ◽  
Large Set ◽  
Strong Binding ◽  
Related Proteins

Natural products from plants such as, chemopreventive agents attract huge attention because of their low toxicity and high specificity. The rational drug design in combination with structure based modeling and rapid screening methods offer significant potential for identifying and developing lead anticancer molecules. Thus, the molecular docking method plays an important role in screening a large set of molecules based on their free binding energies and proposes structural hypotheses of how the molecules can inhibit the target. Several peptide based therapeutics have been developed to combat several health disorders including cancers, metabolic disorders, heart-related, and infectious diseases. Despite the discovery of hundreds of such therapeutic peptides however, only few peptide-based drugs have made it to the market. Moreover, until date the activities of cyclic peptides towards molecular targets such as protein kinases, proteases, and apoptosis related proteins have never been explored. In this study we explore the in silico kinase and protease inhibitor potentials of cyclosaplin as well as study the interactions of cyclosaplin with other cancer-related proteins. Previously, the structure of cyclosaplin was elucidated by molecular modeling associated with dynamics that was used in the current study. Docking studies showed strong affinity of cyclosaplin towards cancer-related proteins. The binding affinity closer to 10 indicated efficient binding. Cyclosaplin showed strong binding affinities towards protein kinases such as EGFR, VEGFR2, PKB and p38 indicating its potential role in protein kinase inhibition. Moreover, it displayed strong binding affinity to apoptosis related proteins and revealed the possible role of cyclosaplin in apoptotic cell death. The protein-ligand interactions using LigPlot displayed some similar interactions between cyclosaplin and peptide-based ligands especially in case of protein kinases and a few apoptosis related proteins. Thus, the in silico analyses gave an insight of cyclosaplin as a potential apoptosis inducer and protein kinase inhibitor.

scholarly journals Estrogenic Effect of Scoparia dulcis (Linn) Extract in Mice Uterus and In Silico Molecular Docking Studies of Certain Compounds with Human Estrogen Receptors

2020 ◽  
Author(s):  
Khamhee Wangsa ◽  
Indira Sarma ◽  
Purbajyoti Saikia ◽  
Dhanabalan Ananthakrishnan ◽  
Hirendra Nath Sarma ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Estrogen Receptors ◽  
Binding Affinity ◽  
In Silico ◽  
Md Simulations ◽  
Docking Studies ◽  
Female Reproduction ◽  
Molecular Docking Studies ◽  
Scoparia Dulcis ◽  
In Silico Molecular Docking

Background: Scoparia dulcis Linn. is reported to be used by women of Assam and Arunachal Pradesh in northeast India for treating menstrual disorders. Scoparia dulcis contains compounds that bind with estrogen receptors (ERα and ERβ) evidenced by increased PCNA in endometrial epithelium. Methods: Crude extract was orally administered at the dose of 500 mg/kg body weight/day to the female mice (60–70 days old) in five different groups. Each group containing six females included: (I) cyclic control, (II) cyclic extract treated, (III) Ovariectomized (OVX)-vehicle treated (Control), (IV) OVX-E2 treated (V) OVX- extract treated. Extract was administered for eight days to the cyclic groups and three days to the OVX groups. PCNA was detected immunohistochemically in uterine tiss ues and signals were analyzed by Image J software (NIH, USA). Compounds were separated by GC-MS and identified using NIST. In silico molecular docking studies was performed with human estrogen receptors (ERα and ERβ). Molecular dynamics (MD) simulations of the best interacting compound was done using gromacs. Results: The results showed cell proliferation in the uterine endometrium evidenced by PCNA. Two phytocompounds, Octadecanoic acid and methyl stearate showed binding affinity with ERα and ERβ. Conclusion: Scoparia dulcis contains compounds having binding affinity with ERα and ERβ. The present study is the first report on compounds from Scoparia dulcis showing binding affinity with human estrogen receptors which may have biological effect on female reproduction.

In silico discovery of novel phytoconstituents of Amyris pinnata as mitotic spindle kinase inhibitor

2020 ◽  
Vol 12 ◽  
Author(s):  
Ghanshyam R. Parmar ◽  
Ashish P. Shah ◽  
Girish U. Sailor ◽  
Avinash Kumar Seth
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Mitotic Spindle ◽  
In Silico ◽  
Kinase Inhibitor ◽  
Pharmacokinetic Profile ◽  
Docking Studies ◽  
Chemotherapeutic Agents ◽  
Cancer Disease ◽  
Molecular Docking Studies

Background: Despite of many successes in discovery of numerous cancer chemotherapeutic agents from natural sources, some of the moieties were dropped because of its inefficiency or serious toxicity. Mitosis is an ordered series of fundamentally mechanical events in which identical copies of the genome are moved to two discrete locations within the dividing cell. The crucial role of the mitotic spindle in cell division has identified which is an important target in cancer chemotherapy. In the present study we are reporting molecular docking studies and in silico pharmacokinetic profile of selected phytoconstituents obtained from Amyris pinnata. Methods: Molecular docking studies of selected phytoconstituents were performed using iGEMDOCK. The crystal structure of protein was exported from protein data bank (PDB id: 4C4H). In silico pharmacokinetic profile of selected phytoconstituents were performed using SWISSADME server. Results: Compound AMNP6 showed higher binding affinity as compared to standard ligand. All the selected phytoconstituents has passed Lipinski rule of five and shown no violations. Conclusion: Good binding affinity and drug likeliness of the AMNP6 suggest that it can be further investigated and explored as mitotic spindle kinase inhibitor in cancer disease.

Virtual Screening of Novel Hybrid Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Exploring Multiple Targeted Cancer Therapy by an In Silico Approach

2020 ◽  
Vol 16 (1) ◽  
pp. 70-77
Author(s):  
Ashish P. Shah ◽  
Chhagan N. Patel
Keyword(s):  
Cancer Therapy ◽  
Virtual Screening ◽  
Binding Affinity ◽  
Anticancer Agents ◽  
In Silico ◽  
Software Tool ◽  
Docking Studies ◽  
Targeted Cancer Therapy ◽  
Bioactivity Prediction ◽  
Glide Docking

Background: Dual-targeting/Multi-targeting of oncoproteins by a single drug molecule represents an efficient, logical and alternative approach to drug combinations. In silico methods are useful tool for the search and design of selective multi-target agents. Objective: The objective of the present study was to design new hybrid compounds by linking the main structural unit of the NSAIDs with the benzothiazole and thiadiazole ring and to discover new hybrid NSAIDs as multi targeted anticancer agents through in silico approach. Method: Structure-based virtual screening was performed by applying ADMET filtration and Glide docking using Virtual screening Workflow. The docking studies were performed on three different types of receptors TNF-α, COX-II and protein kinase. Bioactivity prediction of screened compounds were done using Molinspiration online software tool. Results: Out of 54 designed compounds eighteen were screened on the basis of binding affinity on various receptors and ADMET filtration. Bioactivity prediction reveals that screened compounds may act through kinase inhibition or enzyme inhibition. Compounds 2sa, 5sa, 6sa and 7sa shows higher binding affinity with all three receptors. Conclusion: The study concluded that compound 2sa, 5sa, 6sa, and 7sa could be further explored for multiple targeted cancer therapy.

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