scholarly journals In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening

2022 ◽  
Vol 2022 ◽  
pp. 1-11
Author(s):  
Farzin Hadizadeh ◽  
Razieh Ghodsi ◽  
Salimeh Mirzaei ◽  
Amirhossein Sahebkar
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Critical Role ◽  
Human Tumor ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Microtubule Network ◽  
Acquired Drug Resistance ◽  
Tubulin Inhibitors ◽  
Microtubule Targeting Agents

Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner–Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.

Discovery of potential negative allosteric modulators of mGluR5 from natural products using pharmacophore modeling, molecular docking, and molecular dynamics simulation studies

2015 ◽  
Vol 93 (11) ◽  
pp. 1199-1206 ◽  
Author(s):  
Ludi Jiang ◽  
Yong Li ◽  
Liansheng Qiao ◽  
Xi Chen ◽  
Yusu He ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Natural Products ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Dynamics Simulation ◽  
Allosteric Modulators ◽  
Subtype Selectivity ◽  
Wide Range

mGluR5, which belongs to the G-protein-coupled receptor superfamily, is believed to be associated with many human diseases, such as a wide range of neurological disorders, gastroesophageal reflux disease, and cancer. Comparing with compounds that target on the orthosteric binding site, significant roles have been established for mGluR5 negative allosteric modulators (NAMs) due to their higher subtype selectivity and more suitable pharmacokinetic profiles. Nevertheless, to date, none of them have come to market for various reasons. In this study, a 3D quantitative pharmacophore model was generated by using the HypoGen module in Discovery Studio 4.0. With several validation methods ultilized, the optimal pharmacophore model Hypo2 was selected to discover potential mGluR5 NAMs from natural products. Two hundred and seventeen potential NAMs were obtained after being filtered by Lipinski’s rule (≥4). Then, molecular docking was used to refine the pharmacophore-based screening results and analyze the binding mode of NAMs and mGluR5. Three compounds, aglaiduline, 5-O-ethyl-hirsutanonol, and yakuchinone A, with good ADMET properties, acceptable Fit value and estimated value, and high docking score, were reserved for a molecular dynamics simulation study. All of them have stability of ligand binding. From our computational results, there might exhibit drug-like negative allosteric moderating effects on mGluR5 in these natural products. This work provides a reliable method for discovering mGluR5 NAMs from natural products.

scholarly journals Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, ADMET, and Molecular Dynamics (MD) Simulation of Potential Inhibitors of PD-L1 from the Library of Marine Natural Products

Marine Drugs ◽  
2021 ◽  
Vol 20 (1) ◽  
pp. 29
Author(s):  
Lianxiang Luo ◽  
Ai Zhong ◽  
Qu Wang ◽  
Tongyu Zheng
Keyword(s):  
Molecular Dynamics ◽  
Natural Products ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Marine Natural Products ◽  
Md Simulation ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Dynamics Simulation ◽  
Stable Conformation

Background: In the past decade, several antibodies directed against the PD-1/PD-L1 interaction have been approved. However, therapeutic antibodies also exhibit some shortcomings. Using small molecules to regulate the PD-1/PD-L1 pathway may be another way to mobilize the immune system to fight cancer. Method: 52,765 marine natural products were screened against PD-L1(PDBID: 6R3K). To identify natural compounds, a structure-based pharmacophore model was generated, following by virtual screening and molecular docking. Then, the absorption, distribution, metabolism, and excretion (ADME) test was carried out to select the most suitable compounds. Finally, molecular dynamics simulation was also performed to validate the binding property of the top compound. Results: Initially, 13 small marine molecules were screened based on the pharmacophore model. Then, two compounds were selected for further evaluation based on the molecular docking scores. After ADME and toxicity studies, molecule 51320 was selected for further verification. By molecular dynamics analysis, molecule 51320 maintains a stable conformation with the target protein, so it has the chance to become an inhibitor of PD-L1. Conclusions: Through structure-based pharmacophore modeling, virtual screening, molecular docking, ADMET approaches, and molecular dynamics (MD) simulation, the marine natural compound 51320 can be used as a small molecule inhibitor of PD-L1.

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 ENERGY-BASED PHARMACOPHORE MODELING, VIRTUAL SCREENING, AND MOLECULAR DYNAMICS TO IDENTIFY POTENTIAL INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3 BETA

2018 ◽  
Vol 11 (2) ◽  
pp. 181
Author(s):  
Sheema Jb ◽  
Waheeta Hopper
Keyword(s):  
Molecular Dynamics ◽  
Wound Healing ◽  
Glycogen Synthase ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Systemic Side Effects ◽  
The Stability ◽  
Potential Inhibitors

  Objective: Glycogen synthase kinase 3 beta (GSK3β) is one of the main targets for wound healing activity. Our objective is to identify novel inhibitors for GSK3β using in silico approach.Methods: Grid-based molecular docking, energy-based pharmacophore (e-pharmacophore) modeling, and molecular dynamics (MD) studies were performed for phytocompounds with GSK3β and compared with standard drugs using Schrodinger software.Results: The glide scores and the molecular interactions of the phytocompounds were well comparable to the standard drugs. The MD was performed for the target bound to the best scoring ligand, entagenic acid. The pharmacophore features of this docked complex were modeled as e-pharmacophore. The constructed e-pharmacophore model was screened against phytocompounds retrieved from literature to identify the ligands with similar pharmacophore features.Conclusion: The glide scores of fukinolic acid, cimicifugic acid, and linarin were −10.99, −8.28, and −7.25 kcal/mol, respectively. The further 50 nanoseconds MD study determined the stability of GSK3β-linarin complex. Nitrofurazone and sulfathiazole drugs can lead to systemic side effects. Hence, it is concluded that linarin could be a potent wound healing compound against GSK3β.

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.

scholarly journals Molecular docking, pharmacophore based virtual screening and molecular dynamics studies towards the identification of potential leads for the management of H. pylori

RSC Advances ◽  
2019 ◽  
Vol 9 (45) ◽  
pp. 26176-26208 ◽  
Author(s):  
Manoj G. Damale ◽  
Rajesh B. Patil ◽  
Siddique Akber Ansari ◽  
Hamad M. Alkahtani ◽  
Abdulrahman A. Almehizia ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Md Simulations ◽  
Pharmacophore Modeling ◽  
Gastric Ulcers ◽  
Computational Approaches ◽  
Gastric Cancers ◽  
H Pylori

Computational approaches such as pharmacophore modeling, virtual screening and MD simulations were explored to find the potential hits as H. pylori specific panC inhibitors for the management of gastric ulcers and gastric cancers.

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