scholarly journals Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3171 ◽  
Author(s):  
Vladimir P. Berishvili ◽  
Alexander N. Kuimov ◽  
Andrew E. Voronkov ◽  
Eugene V. Radchenko ◽  
Pradeep Kumar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Ic50 Values ◽  
Energy Perturbation ◽  
Dynamics Simulations

Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.7 M commercially available compounds. Out of seven candidate compounds biologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical assay, two compounds have shown a decent level of inhibitory activity with the IC50 values of less than 10 nM and 10 μM. Relatively simple scores based on molecular docking or MM-PBSA (molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting the effect of structural modification or for accurate ranking of the compounds based on their binding energies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP) calculations allowed us to further decipher the structure-activity relationships and retrospectively analyze the docking-based virtual screening performance. This approach can be applied at the subsequent lead optimization stages.

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.

Advancements in Docking and Molecular Dynamics Simulations Towards Ligand-receptor Interactions and Structure-function Relationships

2018 ◽  
Vol 18 (20) ◽  
pp. 1755-1768 ◽  
Author(s):  
Ahmad Abu Turab Naqvi ◽  
Taj Mohammad ◽  
Gulam Mustafa Hasan ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Computational Method ◽  
Dynamics Simulation ◽  
Ligand Molecule ◽  
Ligand Interaction ◽  
Modern Drug ◽  
Dynamics Simulations

Protein-ligand interaction is an imperative subject in structure-based drug design and protein function prediction process. Molecular docking is a computational method which predicts the binding of a ligand molecule to the particular receptor. It predicts the binding pose, strength and binding affinity of the molecules using various scoring functions. Molecular docking and molecular dynamics simulations are widely used in combination to predict the binding modes, binding affinities and stability of different protein-ligand systems. With advancements in algorithms and computational power, molecular dynamics simulation is now a fundamental tool to investigative bio-molecular assemblies at atomic level. These methods in association with experimental support have been of great value in modern drug discovery and development. Nowadays, it has become an increasingly significant method in drug discovery process. In this review, we focus on protein-ligand interactions using molecular docking, virtual screening and molecular dynamics simulations. Here, we cover an overview of the available methods for molecular docking and molecular dynamics simulations, and their advancement and applications in the area of modern drug discovery. The available docking software and their advancement including application examples of different approaches for drug discovery are also discussed. We have also introduced the physicochemical foundations of molecular docking and simulations, mainly from the perception of bio-molecular interactions.

scholarly journals Coumarin derivatives as acetyl- and butyrylcholinestrase inhibitors: An in vitro, molecular docking, and molecular dynamics simulations study

Heliyon ◽  
2019 ◽  
Vol 5 (4) ◽  
pp. e01552 ◽  
Author(s):  
Marwa N. Abu-Aisheh ◽  
Amal Al-Aboudi ◽  
Mohammad S. Mustafa ◽  
Mustafa M. El-Abadelah ◽  
Saman Yousuf Ali ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Coumarin Derivatives ◽  
Dynamics Simulations

scholarly journals Exploring Aurone Derivatives as Potential Human Pancreatic Lipase Inhibitors through Molecular Docking and Molecular Dynamics Simulations

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4657
Author(s):  
Phuong Thuy Viet Nguyen ◽  
Han Ai Huynh ◽  
Dat Van Truong ◽  
Thanh-Dao Tran ◽  
Cam-Van Thi Vo
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Pancreatic Lipase ◽  
Inhibitory Activity ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Catalytic Active Site ◽  
Dynamics Simulations

Inhibition of human pancreatic lipase, a crucial enzyme in dietary fat digestion and absorption, is a potent therapeutic approach for obesity treatment. In this study, human pancreatic lipase inhibitory activity of aurone derivatives was explored by molecular modeling approaches. The target protein was human pancreatic lipase (PDB ID: 1LPB). The 3D structures of 82 published bioactive aurone derivatives were docked successfully into the protein catalytic active site, using AutoDock Vina 1.5.7.rc1. Of them, 62 compounds interacted with the key residues of catalytic trial Ser152-Asp176-His263. The top hit compound (A14), with a docking score of −10.6 kcal⋅mol−1, was subsequently submitted to molecular dynamics simulations, using GROMACS 2018.01. Molecular dynamics simulation results showed that A14 formed a stable complex with 1LPB protein via hydrogen bonds with important residues in regulating enzyme activity (Ser152 and Phe77). Compound A14 showed high potency for further studies, such as the synthesis, in vitro and in vivo tests for pancreatic lipase inhibitory activity.

scholarly journals Identification of Potential Herbal Inhibitor of Acetylcholinesterase Associated Alzheimer’s Disorders Using Molecular Docking and Molecular Dynamics Simulation

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Chandrabhan Seniya ◽  
Ghulam Jilani Khan ◽  
Kuldeep Uchadia
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Secondary Metabolite ◽  
Therapeutic Potential ◽  
Dynamics Simulation ◽  
Cholinesterase Inhibition ◽  
Ligand Molecule ◽  
Ligand Interaction ◽  
Dynamics Simulations

Cholinesterase inhibitors (ChE-Is) are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA). Additionally, acetylcholinesterase (AChE) is the target for many Alzheimer’s dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite fromCannabisplant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000 ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6) to AChE. Further, molecular dynamics simulations for 1000 ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration ofC28H34N2O6as a valuable small ligand molecule in treatment and prevention of AD associated disorders and furtherin vitroandin vivoinvestigations may prove its therapeutic potential.

Investigations on the mechanisms of interactions between matrix metalloproteinase 9 and its flavonoid inhibitors using a combination of molecular docking, hybrid quantum mechanical/molecular mechanical calculations, and molecular dynamics simulations

2014 ◽  
Vol 92 (9) ◽  
pp. 821-830 ◽  
Author(s):  
Zhi-Guang Zhou ◽  
Qi-Zheng Yao ◽  
Dong Lei ◽  
Qing-Qing Zhang ◽  
Ji Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Biological Activities ◽  
Dynamics Simulation ◽  
Quantum Mechanical ◽  
Free Energies ◽  
Hydrogen Bond Networks ◽  
Dynamics Simulations ◽  
Binding Free Energies

Many experimental studies have found that flavonoids can inhibit the activities of matrix metalloproteinases (MMPs), but the relevant mechanisms are still unclear. In this paper, the interaction mechanisms of MMP-9 with its five flavonoid inhibitors are investigated using a combination of molecular docking, hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, and molecular dynamics simulations. The molecular dynamics simulation results show a good linear correlation between the calculated binding free energies of QM/MM−Poisson–Boltzmann surface area (PBSA) and the experimental −log(EC50) regarding the studied five flavonoids on MMP-9 inhibition in explicit solvent. It is found that compared with the MM−PBSA method, the QM/MM−PBSA method can obviously improve the accuracy for the calculated binding free energies. The predicted binding modes of the five flavonoid−MMP-9 complexes reveal that the different hydrogen bond networks can form besides producing the Zn−O coordination bonds, which can reasonably explain previous experimental results. The agreement between our calculated results and the previous experimental facts indicates that the force field parameters used here are effective and reliable for investigating the systems of flavonoid−MMP-9 interactions, and thus, these simulations and analyses could be reproduced for the other related systems involving protein−ligand interactions. This paper may be helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules.

scholarly journals VIRTUAL SCREENING AND MOLECULAR DYNAMICS SIMULATION OF COMPOUNDS FROM THE HERBAL DATABASE OF INDONESIA AGAINST HISTONE DEACETYLASE 2

2018 ◽  
Vol 10 (1) ◽  
pp. 235
Author(s):  
Muhammad Teguh Setiawan ◽  
Arry Yanuar
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Molecular Dynamics Simulations ◽  
Histone Deacetylase ◽  
Simulation Analysis ◽  
Positive Control ◽  
Dynamics Simulation ◽  
Screening Process ◽  
Histone Deacetylase 2 ◽  
Dynamics Simulations

Objective: This study aimed to find the herbal compounds from the database of Indonesian herbs with potential for use as histone deacetylase 2 (HDAC2)enzyme inhibitors through virtual screening using the LigandScout program.Methods: Virtual screening was conducted using LigandScout 4.09.3, AutodockZN, and AutoDockTools.Results: The virtual screening process resulted in 10 compounds with the highest pharmacophore fit score rating, from which five compounds withthe best criteria for molecular dynamics simulations were selected: Boesenbergin B, pongachalcone I, 6,8-diprenylgenistein, marmin, and mangostin.The ΔG values obtained were, respectively, −8.28, −9.15, −7.05, −9.07, and −7.15. The active crystal ligand N-(2-aminophenyl) benzamide was used asa positive control, with ΔG value of −10.27. Molecular dynamic’s simulations showed that the activity of HDAC2 inhibitors was known to interact inthe amino acid residues His145C, Tyr308C, Zn379C, Leu276C, Phe155C, Phe210C, Leu144C, and Met35C.Conclusions: Based on virtual screening and the molecular dynamics simulations, marmin was considered to provide the best overall activity ofanalysis. Simulation analysis of molecular dynamics from hits compound showed that analysis with MMGBSA gave higher free energy binding valuethan MMPBSA.

scholarly journals Virtual Screening of Phytochemicals by Targeting HR1 Domain of SARS-CoV-2 S Protein: Molecular Docking, Molecular Dynamics Simulations, and DFT Studies

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Arshia Majeed ◽  
Waqar Hussain ◽  
Farkhanda Yasmin ◽  
Ammara Akhtar ◽  
Nouman Rasool
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Density Functional ◽  
Spike Protein ◽  
Effective Vaccine ◽  
High Morbidity ◽  
Dynamics Simulations

The recent COVID-19 pandemic has impacted nearly the whole world due to its high morbidity and mortality rate. Thus, scientists around the globe are working to find potent drugs and designing an effective vaccine against COVID-19. Phytochemicals from medicinal plants are known to have a long history for the treatment of various pathogens and infections; thus, keeping this in mind, this study was performed to explore the potential of different phytochemicals as candidate inhibitors of the HR1 domain in SARS-CoV-2 spike protein by using computer-aided drug discovery methods. Initially, the pharmacological assessment was performed to study the drug-likeness properties of the phytochemicals for their safe human administration. Suitable compounds were subjected to molecular docking to screen strongly binding phytochemicals with HR1 while the stability of ligand binding was analyzed using molecular dynamics simulations. Quantum computation-based density functional theory (DFT) analysis was constituted to analyze the reactivity of these compounds with the receptor. Through analysis, 108 phytochemicals passed the pharmacological assessment and upon docking of these 108 phytochemicals, 36 were screened passing a threshold of -8.5 kcal/mol. After analyzing stability and reactivity, 5 phytochemicals, i.e., SilybinC, Isopomiferin, Lycopene, SilydianinB, and Silydianin are identified as novel and potent candidates for the inhibition of HR1 domain in SARS-CoV-2 spike protein. Based on these results, it is concluded that these compounds can play an important role in the design and development of a drug against COVID-19, after an exhaustive in vitro and in vivo examination of these compounds, in future.

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