In Silico Anticancer Evaluation, Molecular Docking and Pharmacophore Modeling of Flavonoids against Various Cancer Targets

2020 ◽  
Vol 17 (12) ◽  
pp. 1485-1501
Author(s):  
Jainey Puthenveettil James ◽  
Pankaj Kumar ◽  
Abhishek Kumar ◽  
Katte Ishwar Bhat ◽  
Chakrakodi Shashidhara Shastry
Keyword(s):  
Colorectal Cancer ◽  
Lung Cancer ◽  
Molecular Docking ◽  
Anticancer Agents ◽  
In Silico ◽  
Active Sites ◽  
Hydrophobic Interactions ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Score

Background: Designing and development of molecules for cancer treatment useful and with no side effects are a big challenge for the researchers in the field of drug discovery. The use of phytochemicals for chemoprevention is gaining more advantages, and intake of flavonoids has proved to reduce the occurrence of various cancers. Objectives: The present study was focused on selecting eight flavonoids and study them by in silico methods to analyse the interactions, affinity and pharmacophoric features that participate in the interactions between the flavonoid and the active sites of different cancer targets. Methods: The cancer targets were downloaded from the protein data bank, and flavonoids from PubChem and were docked by Glide XP molecular docking method to find the molecular interactions. The binding energy was calculated by Prime MM-GBSA application and ADMET analysis by Qikprop of Schrodinger. The anticancer potential of flavonoids screening was based on an online tool, Pass predictor. Phase module was used to find the common pharmacophore features that participate in essential interactions between the flavonoid and the active site. Results: In this study, myricetin has proved to be the best flavonoid for the treatment of breast and lung cancer with docking score of -11.50 kcal/mol and -10.56 kcal/mol respectively, whereas, quercetin has proved to be the best for prostate and colorectal cancer with docking score of -14.18 kcal/mol and -12.94 kcal/mol, respectively. The responsible forces for the interaction of these flavonoids are hydrogen bond, hydrophobic interactions, polar and pi-pi stackings. The PASS tool predicted the anticancer potential for the flavonoids, in particular, myricetin had responded highly active for most cancer cells. The hypothesis AADRR_1 has the highest survival score, which indicates the best alignment of the active ligands and represents the best pharmacophore model for anticancer activity. Conclusion: This work has screened eight flavonoids against various cancer targets and shown the binding interactions between them, stating that myricetin is the suitable lead candidate for breast and lung cancer; whereas, quercetin is the best lead for prostate and colorectal cancer. And these data are about the results obtained from PASS predictor. Moreover, the pharmacophore model has generated for the flavonoids, which correlate activities with the spatial arrangement of various chemical features. Therefore, this investigation strongly suggests that these flavonoids can be used as leads as anticancer agents.

scholarly journals A Computational Approach towards the Development of Newer Anticancer Agents

2010 ◽  
Vol 7 (1) ◽  
pp. 21-24 ◽  
Author(s):  
Javed I. Sheikh ◽  
H. D. Juneja ◽  
V. N. Ingle
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Anticancer Agents ◽  
In Silico ◽  
Active Sites ◽  
Computational Approach ◽  
The Novel ◽  
Cytochrome P450 Reductase ◽  
P450 Reductase

In silicomolecular docking analyses of the novel 1-(2', 4'-dihydroxy-5'-chlorophenyl)-3-aryl-propane-1, 3-diones were performed in the active sites of enzyme cytochrome P450 reductase to obtain new anticancer agents computationally. 1-(2', 4'-dihydroxy-5'-chlorophenyl)-3-(4"-methoxy-phenyl)-propane-1, 3-dione(3f)was found to have maximum affinity for the active sites of enzyme.

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

2019 ◽  
Vol 15 (5) ◽  
pp. 445-455 ◽  
Author(s):  
Suraj N. Mali ◽  
Sudhir Sawant ◽  
Hemchandra K. Chaudhari ◽  
Mustapha C. Mandewale
Keyword(s):  
Molecular Docking ◽  
Dna Cleavage ◽  
In Silico ◽  
Oral Absorption ◽  
Inhibition Mechanism ◽  
Hydrogen Binding ◽  
Docking Score ◽  
Antibacterial Screening ◽  
Mycobacteria Tuberculosis

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.

scholarly journals Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Firoz A. Dain Md Opo ◽  
Mohammed M. Rahman ◽  
Foysal Ahammad ◽  
Istiak Ahmed ◽  
Mohiuddin Ahmed Bhuiyan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
Md Simulation ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Drug Candidate ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Apoptosis Process

AbstractX-linked inhibitor of apoptosis protein (XIAP) is a member of inhibitor of apoptosis protein (IAP) family responsible for neutralizing the caspases-3, caspases-7, and caspases-9. Overexpression of the protein decreased the apoptosis process in the cell and resulting development of cancer. Different types of XIAP antagonists are generally used to repair the defective apoptosis process that can eliminate carcinoma from living bodies. The chemically synthesis compounds discovered till now as XIAP inhibitors exhibiting side effects, which is making difficulties during the treatment of chemotherapy. So, the study has design to identifying new natural compounds that are able to induce apoptosis by freeing up caspases and will be low toxic. To identify natural compound, a structure-based pharmacophore model to the protein active site cavity was generated following by virtual screening, molecular docking and molecular dynamics (MD) simulation. Initially, seven hit compounds were retrieved and based on molecular docking approach four compounds has chosen for further evaluation. To confirm stability of the selected drug candidate to the target protein the MD simulation approach were employed, which confirmed stability of the three compounds. Based on the finding, three newly obtained compounds namely Caucasicoside A (ZINC77257307), Polygalaxanthone III (ZINC247950187), and MCULE-9896837409 (ZINC107434573) may serve as lead compounds to fight against the treatment of XIAP related cancer, although further evaluation through wet lab is necessary to measure the efficacy of the compounds.

scholarly journals Exploration of Novel Xanthine Oxidase Inhibitors Based on 1,6-Dihydropyrimidine-5-Carboxylic Acids by an Integrated in Silico Study

2021 ◽  
Vol 22 (15) ◽  
pp. 8122
Author(s):  
Na Zhai ◽  
Chenchen Wang ◽  
Fengshou Wu ◽  
Liwei Xiong ◽  
Xiaogang Luo ◽  
...  
Keyword(s):  
Xanthine Oxidase ◽  
Carboxylic Acids ◽  
Hydrophobic Interactions ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Md Simulations ◽  
Pharmacophore Modeling ◽  
Binding Modes ◽  
Comfa Model ◽  
Validation Parameters

Xanthine oxidase (XO) is an important target for the effective treatment of hyperuricemia-associated diseases. A series of novel 2-substituted 6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (ODCs) as XO inhibitors (XOIs) with remarkable activities have been reported recently. To better understand the key pharmacological characteristics of these XOIs and explore more hit compounds, in the present study, the three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) studies were performed on 46 ODCs. The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters, including q2 = 0.897, R2 = 0.983, rpred2 = 0.948 in a CoMFA model, and q2 = 0.922, R2 = 0.990, rpred2 = 0.840 in a CoMSIA model. Docking and MD simulations further gave insights into the binding modes of these ODCs with the XO protein. The results indicated that key residues Glu802, Arg880, Asn768, Thr1010, Phe914, and Phe1009 could interact with ODCs by hydrogen bonds, π-π stackings, or hydrophobic interactions, which might be significant for the activity of these XOIs. Four potential hits were virtually screened out using the constructed pharmacophore model in combination with molecular dockings and ADME predictions. The four hits were also found to be relatively stable in the binding pocket by MD simulations. The results in this study might provide effective information for the design and development of novel XOIs.

scholarly journals STRUCTURE-BASED MULTITARGETED MOLECULAR DOCKING ANALYSIS OF PYRAZOLE-CONDENSED HETEROCYCLICS AGAINST LUNG CANCER

2021 ◽  
pp. 157-169
Author(s):  
JAINEY P. JAMES ◽  
AISWARYA T. C. ◽  
SNEH PRIYA ◽  
DIVYA JYOTHI ◽  
SHESHAGIRI R. DIXIT
Keyword(s):  
Lung Cancer ◽  
Molecular Docking ◽  
Binding Mode ◽  
Pharmacophore Modeling ◽  
In Vivo Studies ◽  
Spectral Studies ◽  
Pyrazole Derivatives ◽  
Anticancer Activities

Objective: The significant drawbacks of chemotherapy are that it destroys healthy cells, resulting in adverse effects. Hence, there is a need to adopt new techniques to develop cancer-specific chemicals that target the molecular pathways in a non-toxic fashion. This study aims to screen pyrazole-condensed heterocyclics for their anticancer activities and analyse their enzyme inhibitory potentials EGFR, ALK, VEGFR and TNKS receptors. Methods: The structures of the compounds were confirmed by IR, NMR and Mass spectral studies. The in silico techniques applied in this study were molecular docking and pharmacophore modeling to analyse the protein-ligand interactions, as they have a significant role in drug discovery. Drug-likeness properties were assessed by the Lipinski rule of five and ADMET properties. Anticancer activity was performed by in vitro MTT assay on lung cancer cell lines. Results: The results confirm that all the synthesised pyrazole derivatives interacted well with the selected targets showing docking scores above-5 kcal/mol. Pyrazole 2e interacted well with all the four lung cancer targets with its stable binding mode and was found to be potent as per the in vitro reports, followed by compounds 3d and 2d. Pharmacophore modeling exposed the responsible features responsible for the anticancer action. ADMET properties reported that all the compounds were found to have properties within the standard limit. The activity spectra of the pyrazoles predicted that pyrazolopyridines (2a-2e) are more effective against specific receptors such as EGFR, ALK and Tankyrase. Conclusion: Thus, this study suggests that the synthesised pyrazole derivatives can be further investigated to validate their enzyme inhibitory potentials by in vivo studies.

scholarly journals Molecular docking analysis of α-Topoisomerase II with δ-Carboline derivatives as potential anticancer agents

2021 ◽  
Vol 17 (1) ◽  
pp. 249-265
Author(s):  
Selvaraj Ayyamperumal ◽  
Keyword(s):  
Molecular Docking ◽  
Anticancer Agents ◽  
Active Sites ◽  
Topoisomerase Ii ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Docking Analysis ◽  
Topo Ii ◽  
Molecular Docking Analysis

The enzyme, α-topoisomerase II (α-Topo II), is known to regulate efficiently the topology of DNA. It is highly expressed in rapidly proliferating cells and plays an important role in replication, transcription and chromosome organisation. This has prompted several investigators to pursue α-Topo II inhibitors as anticancer agents. δ-Carboline, a natural product, and its synthetic derivatives are known to exert potent anticancer activity by selectively targeting α-Topo II. Therefore, it is of interest to design carboline derivatives fused with pyrrolidine-2,5-dione in this context. δ-Carbolines fused with pyrrolidine-2,5-dione are of interest because the succinimide part of fused heteroaromatic molecule can interact with the ATP binding pocket via the hydrogen bond network with selectivity towards α-Topo II. The 300 derivatives designed were subjected to the Lipinski rule of 5, ADMET and toxicity prediction. The designed compounds were further analysed using molecular docking analysis on the active sites of the α-Topo II crystal structure (PDB ID:1ZXM). Molecular dynamic simulations were also performed to compare the binding mode and stability of the protein-ligand complexes. Compounds with ID numbers AS89, AS104, AS119, AS209, AS239, AS269, and AS299 show good binding activity compared to the co-crystal ligand. Molecular Dynamics simulation studies show that the ligand binding to α-Topo II in the ATP domain is stableand the protein-ligand conformation remains unchanged. Binding free energy calculations suggest that seven molecules designed are potential inhibitors for α-Topo II for further consideration as anticancer agents.

IN SILICO CHARACTERIZATION, MOLECULAR DOCKING, AND IN VITRO EVALUATION OF TRIAZOLE DERIVATIVES AS POTENTIAL ANTICANCER AGENTS

2021 ◽  
pp. 22-28
Author(s):  
HARSHITHA T ◽  
VINAY KUMAR T ◽  
VINEETHA T
Keyword(s):  
Molecular Docking ◽  
Anticancer Activity ◽  
Anticancer Agents ◽  
In Silico ◽  
Docking Studies ◽  
Pharmacokinetic Parameters ◽  
Pancreatic Cell ◽  
Triazole Derivatives ◽  
Wet Lab

Objective: The objective of the study was to perform in silico molecular docking and in vitro anticancer studies of proposed 1,2,4-triazole derivatives for the determination of their anticancer activity. Methods: A series of 10 triazole compounds with different substituents were drawn in ACD Lab ChemSketch software. Molecular and biological properties were identified using Molinspiration software. The compounds that obeyed Lipinski rule of five are subjected for pharmacokinetic parameters prediction and docking analysis. SwissDock ADME software is used for the prediction of absorption, distribution, metabolism, and elimination. Then, the compounds are docked with target enzymes in Chimera software 1.14 version. The molecular docking studies revealed favorable molecular interactions and binding energies. The compounds that showed good docking results were synthesized through wet lab synthesis and further preceded for in vitro anticancer studies. Results: Three compounds are selected for wet lab synthesis due to their good docking results compared to other compounds. The synthesized compounds are subjected to different in vitro anticancer studies and found to be having potential anticancer activity. Conclusion: The pharmacokinetic and docking studies conclude that the triazole compounds have potential as anticancer agents. The in vitro anticancer studies revealed that the triazole derivatives are having high potency of anticancer activity against pancreatic cell lines.

Υπολογιστικά εργαλεία για την αναζήτηση νέων βιοδραστικών ενώσεων σε επιλεγμένους πρωτεϊνικούς στόχους

2017 ◽  
Author(s):  
Ευτυχία Κρίτση
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
In Silico ◽  
Pharmacophore Modeling ◽  
Lead Optimization ◽  
Dynamics Simulations ◽  
Hiv 1

Στην παρούσα διατριβή πραγματοποιήθηκε εκτενής μελέτη για την αναζήτηση πρόδρομων βιοδραστικών ενώσεων (hits) από χημικές βιβλιοθήκες για τρείς βιολογικούς στόχους, μέσω της εφαρμογής εμπορικά διαθέσιμων in silico τεχνικών και μεθοδολογιών.Οι στόχοι που επιλέχθηκαν ανήκουν σε διαφορετικές κατηγορίες πρωτεϊνών με μεγάλο φαρμακευτικό ενδιαφέρον, που όμως παρουσιάζουν διαφορετικό επίπεδο ωριμότητας όσον αφορά την εφαρμογή υπολογιστικών εργαλείωνγια την ανακάλυψη νέων φαρμακευτικών ενώσεων. Συγκεριμένα, οι στόχοι που μελετήθηκαν είναι οι ακόλουθοι:•το ένζυμο της 14-α διμεθυλάσης της λανοστερόλης (CYP51) για την αναζήτηση νέων πρόδρομων βιοδραστικών ενώσεων με αντιμικροβιακές ιδιότητες,•το ένζυμο της HIV τύπου 1 πρωτεάσης (HIV-1 PR) για την αναζήτηση νέων πρόδρομων βιοδραστικών ενώσεων με αντι-HIV δράση,•ο διαμεμβρανικός υποδοχέας της Αγγειοτασίνης ΙΙ (ΑΤ1) για την αναζήτηση νέων πρόδρομων βιοδραστικών με αντιυπερτασική δράσηΟι κυριότερες τεχνικές που χρησιμοποιήθηκαν για την αναζήτηση πρόδρομων βιοδραστικών ενώσεων περιλαμβάνουν την Εικονική Σάρωση (Virtual Screening) με χρήση Φαρμακοφόρων Μοντέλων (Pharmacophore modeling), τη Μοριακή Πρόσδεση (Molecular Docking), την πρόβλεψη μοριακών ιδιοτήτων καθώς και Προσομοιώσεις Μοριακής Δυναμικής (Molecular Dynamics Simulations). Η στρατηγική που ακολουθήθηκε διαφέρει σημαντικά ανά στόχο όσον αφορά τη μεθοδολογική προσέγγιση και την επιλογή των υπολογιστικών εργαλείων-αλγορίθμων, δίνοντας έμφαση στη συμπληρωματικότητα των αποτελεσμάτων τους. Για την ανάδειξη των πρόδρομων βιοδραστικών ενώσεων, πραγματοποιήθηκαν in vitro βιολογικές δοκιμές των ενώσεων που προτάθηκαν μέσω των υπολογιστικών τεχνικών. Οι ενώσεις που επιλέχθηκαν παρουσίασαν ανασταλτική δράση (ή συγγένεια πρόσδεσης) σε ικανοποιητικό εύρος τιμών 102 nM–μΜ για να χαρακτηριστούν πρόδρομες βιοδραστικές. Μείζονος σημασίας είναι και το γεγονός ότι οι δομικοί σκελετοί των προτεινόμενων ενώσεων για κάθε στόχο, είναι διαφορετικοί τόσο μεταξύ τους όσο και συγκρινόμενοι με τα υφιστάμενα φαρμακευτικά μόρια. Ως εκ τούτου, μπορούν να αποτελέσουν κατάλληλα "υποστρώματα" για το επόμενο στάδιο που αφορά τη βελτιστοποίησή τους προς ενώσεις-οδηγούς (hit to lead optimization) και δυνητικά προς νέα φαρμακευτικά προϊόντα.

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