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

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

10.12681/eadd/40331 ◽

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

Heliyon ◽

10.1016/j.heliyon.2019.e01552 ◽

2019 ◽

Vol 5 (4) ◽

pp. e01552 ◽

Cited By ~ 6

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

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

Molecules ◽

10.3390/molecules25204657 ◽

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.

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Interaction of the TonB dependent transporter HasR with its cognate TonB-like protein HasB in a membrane environment

10.1101/2021.04.21.440789 ◽

2021 ◽

Author(s):

Kamolrat Somboon ◽

Oliver Melling ◽

Maylis Lejeune ◽

Glaucia M.S. Pinheiro ◽

Annick Paquelin ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Protein Dynamics ◽

Periplasmic Space ◽

Geometrical Constraints ◽

Flexible Region ◽

Tonb Protein ◽

Dynamics Simulations

Energized nutrient import in bacteria needs the interaction between a TonB-dependent transporter (TBDT) and a TonB protein. The mechanism of energy and signal transfer between these two proteins is not well understood. They belong to two membranes separated by the periplasmic space and possess each a disordered and flexible region. Therefore, the membranes, their distance and geometrical constraints together with the protein dynamics are important factors for deciphering this trans-envelope system. Here we report the first example of the interaction of a TBDT with a TonB protein in the presence of both membranes. By combining molecular dynamics simulations in a membrane model, in vitro and in vivo phenotypic experiments we obtained the comprehensive network of interaction between HasR, a heme/hemophore receptor and its dedicated TonB protein, HasB.

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Ginger (Zingiber officinale) phytochemicals—gingerenone-A and shogaol inhibit SaHPPK: molecular docking, molecular dynamics simulations and in vitro approaches

Annals of Clinical Microbiology and Antimicrobials ◽

10.1186/s12941-018-0266-9 ◽

2018 ◽

Vol 17 (1) ◽

Cited By ~ 7

Author(s):

Shailima Rampogu ◽

Ayoung Baek ◽

Rajesh Goud Gajula ◽

Amir Zeb ◽

Rohit S. Bavi ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

Zingiber Officinale ◽

Dynamics Simulations

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

Molecules ◽

10.3390/molecules25143171 ◽

2020 ◽

Vol 25 (14) ◽

pp. 3171 ◽

Cited By ~ 4

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.

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Identification of Potential Binders of the SARS-Cov-2 Spike Protein via Molecular Docking, Dynamics Simulation and Binding Free Energy Calculation

10.26434/chemrxiv.12278588 ◽

2020 ◽

Author(s):

Dr. Chirag N. Patel ◽

Dr. Prasanth Kumar S. ◽

Dr. Himanshu A. Pandya ◽

Dr. Rakesh M. Rawal

Keyword(s):

Molecular Dynamics ◽

Free Energy ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

Binding Free Energy ◽

Free Energy Calculations ◽

Dynamics Simulation ◽

Spike Protein ◽

Energy Calculations ◽

Dynamics Simulations

<p>The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.</p>

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Evaluating Phenyl Propanoids Isolated from Citrus medica as Potential Inhibitors for Mitotic kinesin Eg5

Letters in Drug Design & Discovery ◽

10.2174/1570180817999200630125449 ◽

2020 ◽

Vol 17 (11) ◽

pp. 1355-1363

Author(s):

Himesh Makala ◽

Venkatasubramanian Ulaganathan ◽

Aravind Sivasubramanian ◽

Narendran Rajendran ◽

Shankar Subramanian

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulations ◽

Strong Basis ◽

Citrus Medica ◽

Kinesin Eg5 ◽

Dynamics Simulations ◽

Pharmacologically Active ◽

Mitotic Kinesin Eg5

Background: Human mitotic kinesins play an essential role in mitotic cell division. Targeting the spindle separation phase of mitosis has gained much attention in cancer chemotherapy. Spindle segregation is carried out mainly by the kinesin, Eg5. Many Eg5 inhibitors are in different phases of clinical trials as cancer drugs. This enzyme has two allosteric binding sites to which the inhibitors can bind. The first site is formed by loop L5, helix α2 and helix α3 and all the current drug candidates bind un-competitively to this site with ATP/ADP. The second site, formed by helix α4 and helix α6, which has gained attention recently, has not been explored well. Some inhibitors that bind to this site are competitive, while others are uncompetitive to ATP/ADP. Phenylpropanoids are pharmacologically active secondary metabolites. Methods: In this study, we have evaluated fourteen phenyl propanoids extracted from Citrus medica for inhibitory activity against human mitotic kinesin Eg5 in vitro steady-state ATPase assay. Ther interactions and stability using molecular docking and molecular dynamics simulations. Results and Discussions: Of the fourteen compounds tested, naringin and quercetin showed good activity with IC50 values in the micromolar range. Molecular docking studies of these complexes showed that both the molecules interact with the key residues of the active site predominantly thorough hydrophobic & aromatic π–π interactions consistent with the known inhibitors. Besides, these molecules also form hydrogen bonding interactions stabilizing the complexes. Molecular dynamics simulations of these complexes confirm the stability of these interactions. Conclusion: These results can be used as a strong basis for further modification of these compounds to design new inhibitors with higher potency using structure-based drug design.

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Conserved α-helix-3 is crucial for structure and functions of Rad6 E2 ubiquitin-conjugating enzymes

10.1101/2021.10.12.464121 ◽

2021 ◽

Author(s):

Prakash K. Shukla ◽

Dhiraj Sinha ◽

Andrew M. Leng ◽

Jesse E. Bissell ◽

Shravya Thatipamula ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Biological Functions ◽

Conjugating Enzymes ◽

Α Helix ◽

Dynamics Simulations ◽

Ubiquitin Conjugating Enzymes ◽

Structure And Activity

AbstractRad6, an E2 ubiquitin-conjugating enzyme conserved from yeast to humans, functions in transcription, genome maintenance and proteostasis. The contributions of many conserved secondary structures of Rad6 and its human homologs UBE2A and UBE2B to their biological functions are not understood. A mutant RAD6 allele with a missense substitution at alanine-126 (A126) of α-helix-3 that causes defects in telomeric gene silencing, DNA repair and protein degradation was reported over two decades ago. Here, using a combination of genetics, biochemical, biophysical, and computational approaches, we discovered that α-helix-3 A126 mutations compromise the ability of Rad6 to ubiquitinate target proteins without disrupting interactions with partner E3 ubiquitin-ligases that are required for their various biological functions in vivo. Explaining the defective in vitro or in vivo ubiquitination activities, molecular dynamics simulations and NMR showed that α-helix-3 A126 mutations cause local disorder of the catalytic pocket of Rad6, and also disorganize the global structure of the protein to decrease its stability in vivo. We further demonstrate that α-helix-3 A126 mutations deform the structures of UBE2A and UBE2B, the human Rad6 homologs, and compromise the in vitro ubiquitination activity and folding of UBE2B. Molecular dynamics simulations and circular dichroism spectroscopy along with functional studies further revealed that cancer-associated mutations in α-helix-3 of UBE2A or UBE2B alter both structure and activity, providing an explanation for their pathogenicity. Overall, our studies reveal that the conserved α-helix-3 is a crucial structural constituent that controls the organization of catalytic pockets and biological functions of the Rad6-family E2 ubiquitin-conjugating enzymes.HighlightsContributions of the conserved α-helix-3 to the functions of E2 enzymes is not known.Mutations in alanine-126 of α-helix-3 impair in vitro enzymatic activity and in vivo biological functions of Rad6.Mutations in alanine-126 of α-helix-3 disorganize local or global protein structure, compromise folding or stability, and impair the catalytic activities of yeast Rad6 and its human homologs UBE2A and UBE2B.Cancer-associated mutations in α-helix-3 of human UBE2A or UBE2B alter protein flexibility, structure, and activity.α-helix-3 is a key structural component of yeast and human Rad6 E2 ubiquitin-conjugating enzymes.

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