scholarly journals Human Hyal‑1 – from in silico Pharmacophore Modeling to in vitro Inhibitor Screening

2017 ◽  
Author(s):  
Isabelle Lengers ◽  
Fabian Herrmann ◽  
Samer Haidar ◽  
Joachim Jose
Keyword(s):  
In Silico ◽  
Pharmacophore Modeling ◽  
Inhibitor Screening

In Silico Identification and in Vitro Validation of Potential Cholestatic Compounds through 3D Ligand-Based Pharmacophore Modeling of BSEP Inhibitors

2014 ◽  
Vol 27 (5) ◽  
pp. 873-881 ◽  
Author(s):  
Tina Ritschel ◽  
Susanne M. A. Hermans ◽  
Marieke Schreurs ◽  
Jeroen J. M. W. van den Heuvel ◽  
Jan B. Koenderink ◽  
...  
Keyword(s):  
In Silico ◽  
Pharmacophore Modeling ◽  
In Silico Identification

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 Pharmacophore based drug designing of COL7A1; The causative gene of Dystrophic Epidermolysis Bullosa

2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Yasra Fatima ◽  
Muhammad Aqib Shabbir ◽  
Noor-ul-Ain ◽  
Syeda Izma Makhdoom ◽  
Hamza Saleem-ur-Rehman ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
In Silico ◽  
Genetic Disorder ◽  
3D Structure ◽  
Pharmacophore Modeling ◽  
Chain Gene ◽  
Causative Gene ◽  
Dystrophic Epidermolysis Bullosa

Epidermolysis Bullosa is a rare genetic disorder that causes skin fragility, trauma induced dissociations of the skin, and painful wound growth. More than 20 types of genes are involved in causing EB as it is a polygenic disease and each gene is involved in a different subtype of EB. Dystrophic Epidermolysis Bullosa (DEB) is one of the subtypes of EB caused by mutations in the COL7A1 (Collagen Type VII Alpha 1 Chain) gene and it affects people from all racial backgrounds. No drug is available for DEB in the market yet. So, it is the need of the hour to come up with a potential inhibitor that could inhibit the faulty protein of COL7A1 gene. Different exons of COL7A1 have been analyzed and exon no 70 to 75 has been selected which were important for mutational point of view. The mutations in it have been identified and verified using various In-silico tools. The 3D structure of the protein has been retrieved using specific exons which were edited and mutations were introduced in it and it was further checked to analyze its stability, toxicity and solubility of the protein. The inhibitors of COL7A1 have been formed using CAAD techniques (pharmacophore modeling) and the best inhibitor of COL7A1 has been further checked to determine its drug-likeness, solubility, its toxicity, and various physiochemical properties. The constructed inhibitor was found to have the best docking results and found to have good ADMET properties. The developed inhibitor construct showing promising results In-silico and it will also show good results if it would be tested in-vitro and in-vivo. Thus, it would be a breakthrough to treat DEB using this inhibitor if this inhibitor is constructed and further tested in-vitro.

Momordica charantia and breast cancer: An in silico approach

2020 ◽  
Vol 19 (06) ◽  
pp. 2050015
Author(s):  
Malênia Oliveira dos Santos Coelho ◽  
Caroline de Almeida Berbert ◽  
Leonardo Luiz Borges
Keyword(s):  
Breast Cancer ◽  
Phenolic Compounds ◽  
In Silico ◽  
Biological Activities ◽  
Pharmacophore Modeling ◽  
Momordica Charantia ◽  
Ovarian Cancers ◽  
Potential Efficacy

Momordica charantia, known as “São Caetano Melon”, is a medicinal plant popularly used for its antitumor, anticarcinogenic, hypoglycemic, and other properties. Studies in mice have demonstrated its activity in vivo against breast, prostate, and ovarian cancers. In vitro studies have also indicated potential efficacy against cervical solid tumors, and breast cancer. In these studies, we sought to evaluate these putative activities. Our methods included use of in silico tools to assess predicted biological activities, pharmacodynamics, and toxicity. We also performed docking and pharmacophore modeling studies. We found phenolic compounds, flavonoids, alkaloids, and triterpenes. Four flavonoids possess predicted anticarcinogenic activity, and affinity for estrogen receptors. Quercetin was selected for the study because it is the most prevalent representative of its class.

scholarly journals Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors

2017 ◽  
Vol 5 ◽  
Author(s):  
Muhammad Akram ◽  
Watcharee Waratchareeyakul ◽  
Joerg Haupenthal ◽  
Rolf W. Hartmann ◽  
Daniela Schuster
Keyword(s):  
Cytochrome P450 ◽  
In Silico ◽  
Pharmacophore Modeling ◽  
In Vitro Screening ◽  
Human Cytochrome

IN VITRO/IN SILICO CHARACTERIZATION OF ACTIVE AND PASSIVE STRESSES IN CARDIAC MUSCLE

2012 ◽  
Vol 10 (2) ◽  
pp. 171-188 ◽  
Author(s):  
Markus Boel ◽  
Oscar J. Abilez ◽  
Ahmed N Assar ◽  
Christopher K. Zarins ◽  
Ellen Kuhl
Keyword(s):  
Cardiac Muscle ◽  
In Silico ◽  
In Silico Characterization

Role of 4-O Galloylchlorogenic Acid in Lung Cancer- An Insilico Approach

2017 ◽  
Vol 9 (5) ◽  
Author(s):  
Jaynthy C. ◽  
N. Premjanu ◽  
Abhinav Srivastava
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
In Silico ◽  
Computational Study ◽  
Regulation Mechanism ◽  
Down Regulation ◽  
Fruit Extract ◽  
In Vitro Techniques ◽  
Discovery Studio

Cancer is a major disease with millions of patients diagnosed each year with high mortality around the world. Various studies are still going on to study the further mechanisms and pathways of the cancer cell proliferation. Fucosylation is one of the most important oligosaccharide modifications involved in cancer and inflammation. In cancer development increased core fucosylation by FUT8 play an important role in cell proliferation. Down regulation of FUT8 expression may help cure lung cancer. Therefore the computational study based on the down regulation mechanism of FUT8 was mechanised. Sapota fruit extract, containing 4-Ogalloylchlorogenic acid was used as the inhibitor against FUT-8 as target and docking was performed using in-silico tool, Accelrys Discovery Studio. There were several conformations of the docked result, and conformation 1 showed 80% dock score between the ligand and the target. Further the amino acids of the inhibitor involved in docking were studied using another tool, Ligplot. Thus, in-silico analysis based on drug designing parameters shows that the fruit extract can be studied further using in-vitro techniques to know its pharmacokinetics.

Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations

2019 ◽  
Author(s):  
Filip Fratev ◽  
Denisse A. Gutierrez ◽  
Renato J. Aguilera ◽  
suman sirimulla
Keyword(s):  
Virtual Screening ◽  
Success Rate ◽  
Protein Interactions ◽  
In Silico ◽  
Biological Data ◽  
In Vitro Binding ◽  
Vitro Binding ◽  
Screening Protocol ◽  
Screening Approaches

AKT1 is emerging as a useful target for treating cancer. Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines structure-based pharmacophore and docking screens. Taking together with the biological data, the combination of structure based pharamcophore and docking methods demonstrated reasonable success rate in identifying new inhibitors (60-70%) proving the success of aforementioned approach. A detail analysis of the ligand-protein interactions was performed explaining observed activities.<br>

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