In vitro inhibition studies of coumarin derivatives on Bos taurus enolase and elucidating their interaction by molecular docking, molecular dynamics simulations and MMGB(PB)SA binding energy calculation

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

BioMed Research International ◽

10.1155/2021/6661191 ◽

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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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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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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Molecular Basis of Iterative C–H Oxidation by TamI, a Multifunctional P450 Monooxygenase from the Tirandamycin Biosynthetic Pathway

10.26434/chemrxiv.12710159.v1 ◽

2020 ◽

Author(s):

Sean A. Newmister ◽

Kinshuk Raj Srivastava ◽

Rosa V. Espinoza ◽

Kersti Caddell Haatveit ◽

Yogan Khatri ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Molecular Basis ◽

Hydrophobic Interactions ◽

Cytochromes P450 ◽

Targeted Mutagenesis ◽

P450 Monooxygenase ◽

Bond Functionalization ◽

Dynamics Simulations

Biocatalysis offers an expanding and powerful strategy to construct and diversify complex molecules by C-H bond functionalization. Due to their high selectivity, enzymes have become an essential tool for C-H bond functionalization and offer complementary reactivity to small-molecule catalysts. Hemoproteins, particularly cytochromes P450, have proven effective for selective oxidation of unactivated C-H bonds. Previously, we reported the in vitro characterization of an oxidative tailoring cascade in which TamI, a multifunctional P450 functions co-dependently with the TamL flavoprotein to catalyze regio- and stereoselective hydroxylations and epoxidation to yield tirandamycin A and tirandamycin B. TamI follows a defined order including 1) C10 hydroxylation, 2) C11/C12 epoxidation, and 3) C18 hydroxylation. Here we present a structural, biochemical, and computational investigation of TamI to understand the molecular basis of its substrate binding, diverse reactivity, and specific reaction sequence. The crystal structure of TamI in complex with tirandamycin C together with molecular dynamics simulations and targeted mutagenesis suggest that hydrophobic interactions with the polyene chain of its natural substrate are critical for molecular recognition. QM/MM calculations and molecular dynamics simulations of TamI with variant substrates provided detailed information on the molecular basis of sequential reactivity, and pattern of regio- and stereo-selectivity in catalyzing the three-step oxidative cascade.

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Assessing the Antimalarial Potentials of Phytochemicals: Virtual Screening, Molecular Dynamics and In-Vitro Investigations

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180604085626 ◽

2019 ◽

Vol 16 (3) ◽

pp. 291-300

Author(s):

Saumya K. Patel ◽

Mohd Athar ◽

Prakash C. Jha ◽

Vijay M. Khedkar ◽

Yogesh Jasrai ◽

...

Keyword(s):

Molecular Dynamics ◽

Structural Integrity ◽

Md Simulations ◽

Tylophora Indica ◽

Multidrug Resistance Protein 1 ◽

Receptor Complexes ◽

Resistance Protein ◽

Dynamics Simulations ◽

Stable Trajectory

Background: Combined in-silico and in-vitro approaches were adopted to investigate the antiplasmodial activity of Catharanthus roseus and Tylophora indica plant extracts as well as their isolated components (vinblastine, vincristine and tylophorine). Methods: We employed molecular docking to prioritize phytochemicals from a library of 26 compounds against Plasmodium falciparum multidrug-resistance protein 1 (PfMDR1). Furthermore, Molecular Dynamics (MD) simulations were performed for a duration of 10 ns to estimate the dynamical structural integrity of ligand-receptor complexes. Results: The retrieved bioactive compounds viz. tylophorine, vinblastin and vincristine were found to exhibit significant interacting behaviour; as validated by in-vitro studies on chloroquine sensitive (3D7) as well as chloroquine resistant (RKL9) strain. Moreover, they also displayed stable trajectory (RMSD, RMSF) and molecular properties with consistent interaction profile in molecular dynamics simulations. Conclusion: We anticipate that the retrieved phytochemicals can serve as the potential hits and presented findings would be helpful for the designing of malarial therapeutics.

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