Identification of High-affinity Small Molecules Targeting Gamma Secretase for the Treatment of Alzheimer’s Disease

2019 ◽  
Vol 19 (13) ◽  
pp. 1173-1187 ◽  
Author(s):  
Meer Asif Ali ◽  
Sugunakar Vuree ◽  
Himshikha Goud ◽  
Tajamul Hussain ◽  
Anuraj Nayarisseri ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Amyloid Plaques ◽  
Docking Studies ◽  
Screening Methods ◽  
Docking Site ◽  
Gamma Secretase ◽  
Pharmacophore Mapping ◽  
High Affinity ◽  
Main Component

Background: Alzheimers Disease (AD) is a neurodegenerative disease which is characterized by the deposition of amyloid plaques in the brain- a concept supported by most of the researchers worldwide. The main component of the plaques being amyloid-beta (Aβ42) results from the sequential cleavage of Amyloid precursor protein (APP) by beta and gamma secretase. This present study intends to inhibit the formation of amyloid plaques by blocking the action of gamma secretase protein with Inhibitors (GSI). Methods: A number of Gamma Secretase Inhibitors (GSI) were targeted to the protein by molecular docking. The inhibitor having the best affinity was used as a subject for further virtual screening methods to obtain similar compounds. The generated compounds were docked again at the same docking site on the protein to find a compound with higher affinity to inhibit the protein. The highlights of virtually screened compound consisted of Pharmacophore Mapping of the docking site. These steps were followed by comparative assessments for both the compounds, obtained from the two aforesaid docking studies, which included interaction energy descriptors, ADMET profiling and PreADMET evaluations. Results: 111 GSI classified as azepines, sulfonamides and peptide isosteres were used in the study. By molecular docking an amorpholino-amide, compound (22), was identified to be the high affinity compound GSI along with its better interaction profiles.The virtually screened pubchem compound AKOS001083915 (CID:24462213) shows the best affinity with gamma secretase. Collective Pharmacophore mapping (H bonds, electrostatic profile, binding pattern and solvent accesibility) shows a stable interaction. The resulting ADMETand Descriptor values were nearly equivalent. Conclusion: These compounds identified herein hold a potential as Gamma Secretase inhibitors.According to PreADMET values the compound AKOS001083915 is effective and specific to the target protein. Its BOILED-egg plot analysis infers the compound permeable to blood brain barrier.Comparative study for both the compounds resulted in having nearly equivalent properties. These compounds have the capacity to inhibit the protein which is indirectly responsible for the formation of amyloid plaques and can be further put to in vitro pharmacokinetic and dynamic studies.

Evaluation of Cytotoxic and Tyrosinase Inhibitory Activities of 2-phenoxy(thiomethyl) pyridotriazolopyrimidines: In Vitro and Molecular Docking Studies

2020 ◽  
Vol 20 (14) ◽  
pp. 1714-1721
Author(s):  
Hatem A. Abuelizz ◽  
El Hassane Anouar ◽  
Mohamed Marzouk ◽  
Mizaton H. Hasan ◽  
Siti R. Saleh ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Kojic Acid ◽  
Docking Studies ◽  
Breast Adenocarcinoma ◽  
Amino Acid Residues ◽  
New Class ◽  
Structure Activity ◽  
Tyrosinase Inhibitors ◽  
Mcf 7

Background: The use of tyrosinase has confirmed to be the best means of recognizing safe, effective, and potent tyrosinase inhibitors for whitening skin. Twenty-four 2-phenoxy(thiomethyl)pyridotriazolopyrimidines were synthesized and characterized in our previous studies. Objective: The present work aimed to evaluate their cytotoxicity against HepG2 (hepatocellular carcinoma), A549 (pulmonary adenocarcinoma), MCF-7 (breast adenocarcinoma) and WRL 68 (embryonic liver) cell lines. Methods: MTT assay was employed to investigate the cytotoxicity, and a tyrosinase inhibitor screening kit was used to evaluate the Tyrosinase (TYR) inhibitory activity of the targets. Results: The tested compounds exhibited no considerable cytotoxicity, and nine of them were selected for a tyrosinase inhibitory test. Compounds 2b, 2m, and 5a showed good inhibitory percentages against TYR compared to that of kojic acid (reference substance). Molecular docking was performed to rationalize the Structure-Activity Relationship (SAR) of the target pyridotriazolopyrimidines and analyze the binding between the docked-selected compounds and the amino acid residues in the active site of tyrosinase. Conclusion: The target pyridotriazolopyrimidines were identified as a new class of tyrosinase inhibitors.

Molecular docking studies of tea (Thea sinensis Linn.) polyphenols inhibition pattern with Rat P-glycoprotein

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Babar Ali ◽  
Qazi Mohammad Sajid Jamal ◽  
Showkat R. Mir ◽  
Saiba Shams ◽  
Mohammad Amjad Kamal
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Binding Energy ◽  
Oral Administration ◽  
Docking Studies ◽  
Vital Role ◽  
Glycoprotein P ◽  
High Affinity ◽  
P Glycoprotein ◽  
Inhibition Pattern

AbstractSince 3000 B.C., evergreen plant Thea sinensis (Theaceae) is used both as a social and medicinal beverage. Leaves of T. sinensis contain amino acids, vitamins, caffeine, polysaccharides and polyphenols. Most of the natural medicinal actions of tea are due to the availability and abundance of polyphenols mainly catechins. It has also been stated that some catechins were absorbed more rapidly than other compounds after the oral administration of tea and could increase the bio-enhancing activities of anticancer drugs by inhibiting P-glycoprotein (P-gp). The results of the molecular docking showed that polyphenols bind easily to the active P-gp site. All compounds exhibited fluctuating binding affinity ranged from −11.67 to −8.36 kcal/mol. Observed binding energy required for theaflavin to bind to P-gp was lowest (−11.67 kcal/mol). The obtained data that supports all the selected polyphenols inhibited P-gp and therefore may enhance the bioavailability of drugs. This study may play a vital role in finding hotspots in P-gp and eventually may be proved useful in designing compounds with high affinity and specificity to the protein.

scholarly journals In silico molecular docking and in vitro antimicrobial efficacy of phytochemicals against multi-drug-resistant enteroaggregative Escherichia coli and non-typhoidal Salmonella spp.

Gut Pathogens ◽  
2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Padikkamannil Abishad ◽  
Pollumahanti Niveditha ◽  
Varsha Unni ◽  
Jess Vergis ◽  
Nitin Vasantrao Kurkure ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Molecular Docking ◽  
In Silico ◽  
Docking Studies ◽  
Antimicrobial Efficacy ◽  
Drug Resistant ◽  
Protein Motifs ◽  
Phytochemical Compounds ◽  
In Silico Molecular Docking

Abstract Background In the wake of emergence of antimicrobial resistance, bioactive phytochemical compounds are proving to be important therapeutic agents. The present study envisaged in silico molecular docking as well as in vitro antimicrobial efficacy screening of identified phytochemical ligands to the dispersin (aap) and outer membrane osmoporin (OmpC) domains of enteroaggregative Escherichia coli (EAEC) and non-typhoidal Salmonella spp. (NTS), respectively. Materials and methods The evaluation of drug-likeness, molecular properties, and bioactivity of the identified phytocompounds (thymol, carvacrol, and cinnamaldehyde) was carried out using Swiss ADME, while Protox-II and StopTox servers were used to identify its toxicity. The in silico molecular docking of the phytochemical ligands with the protein motifs of dispersin (PDB ID: 2jvu) and outer membrane osmoporin (PDB ID: 3uu2) were carried out using AutoDock v.4.20. Further, the antimicrobial efficacy of these compounds against multi-drug resistant EAEC and NTS strains was determined by estimating the minimum inhibitory concentrations and minimum bactericidal concentrations. Subsequently, these phytochemicals were subjected to their safety (sheep and human erythrocytic haemolysis) as well as stability (cationic salts, and pH) assays. Results All the three identified phytochemicals ligands were found to be zero violators of Lipinski’s rule of five and exhibited drug-likeness. The compounds tested were categorized as toxicity class-4 by Protox-II and were found to be non- cardiotoxic by StopTox. The docking studies employing 3D model of dispersin and ompC motifs with the identified phytochemical ligands exhibited good binding affinity. The identified phytochemical compounds were observed to be comparatively stable at different conditions (cationic salts, and pH); however, a concentration-dependent increase in the haemolytic assay was observed against sheep as well as human erythrocytes. Conclusions In silico molecular docking studies provided useful insights to understand the interaction of phytochemical ligands with protein motifs of pathogen and should be used routinely before the wet screening of any phytochemicals for their antibacterial, stability, and safety aspects.

Synthesis, in vitro evaluation and molecular docking studies of thiazole derivatives as new inhibitors of α-glucosidase

2015 ◽  
Vol 62 ◽  
pp. 15-21 ◽  
Author(s):  
Fazal Rahim ◽  
Hayat Ullah ◽  
Muhammad Tariq Javid ◽  
Abdul Wadood ◽  
Muhammad Taha ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Studies ◽  
Thiazole Derivatives ◽  
In Vitro Evaluation ◽  
Molecular Docking Studies

Antioxidant, antimicrobial, and molecular docking studies of novel chalcones and Schiff bases bearing 1, 4-naphthoquinone moiety

2021 ◽  
Vol 19 ◽  
Author(s):  
Nadia Ali Ahmed Elkanzi ◽  
Hajer Hrichi ◽  
Rania B. Bakr
Keyword(s):  
Molecular Docking ◽  
Schiff Bases ◽  
Active Sites ◽  
Radical Scavenging ◽  
Docking Studies ◽  
Antimicrobial Compounds ◽  
Molecular Docking Studies ◽  
Fungal Strains ◽  
Chemical Structures

Background: The 1,4-naphthoquinone ring has attracted prominent interest in the field of medicinal chemistry due to its potent pharmacological activity as antioxidant, antibacterial, antifungal, and anticancer. Objective: Herein, a series of new Schiff bases (4-6) and chalcones (8a-c & 9a-d) bearing 1,4-naphthoquinone moiety were synthesized in good yields and were subjected to in-vitro antimicrobial, antioxidant, and molecular docking testing. Methods: A facile protocol has been described in this study for the synthesis of new derivatives (4-7, 8a-c, and 9a-d) bearing 1,4-naphthoquinone moiety. The chemical structures of all the synthesized compounds were identified by 1H-NMR, 13C-NMR, MS, and elemental analyses. Moreover, these derivatives were assessed for their in-vitro antimicrobial activity against gram-positive, gram-negative bacteria, and fungal strains. Further studies were conducted to test their antioxidant activity using DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging assay. Molecular docking studies were realized to identify the most likely interactions of the novel compounds within the protein receptor. Results: The antimicrobial results showed that most of the compounds displayed good efficacy against both bacterial and fungal strains. The antioxidant study revealed that compounds 9d, 9a, 9b, 8c, and 6 exhibited the highest radical scavenging activity. Docking studies of the most active antimicrobial compounds within GLN- 6-P, recorded good scores with several binding interactions with the active sites. Conclusion: Based on the obtained results, it was found that compounds 8b, 9b, and 9c displayed the highest activity against both bacterial and fungal strains. The obtained findings from the DPPH radical scavenging method revealed that compounds 9d and 9a exhibited the strongest scavenging potential. The molecular docking studies proved that the most active antimicrobial compounds 8b, 9b and 9c displayed the highest energy binding scores within the glucosamine-6-phosphate synthase (GlcN-6-P) active site.

scholarly journals SUSTAINED RELEASE TABLETS OF SORAFENIB-SILIBININ COMBINATIONS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA

2018 ◽  
Vol 10 (5) ◽  
pp. 117
Author(s):  
Savita Mishra ◽  
Sandhya Hora ◽  
Vibha Shukla ◽  
Mukul Das ◽  
Harsha Kharkwal ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Release ◽  
Sustained Release ◽  
Cell Line ◽  
Binding Affinity ◽  
Drug Combination ◽  
Docking Studies ◽  
Molecular Docking Studies ◽  
Weight Variation

Objective: The aim of this study was to develop polymer coated sustained release tablet using sorafenib and silibinin combination for the treatment of hepatocellular carcinoma.Methods: The qualitative analysis such as weight variation, friability, hardness, interaction studies, disintegration and in vitro release were performed to validate formulated tablets. We have maintained the acceptable official limits for weight variation, friability, hardness and disintegration time according to prescribed pharmacopoeial recommendation. In vitro drug release studies were performed using USP-II (paddle type) dissolution apparatus. The MTT assay was performed for assessment of Cell viability of drug combination for tablet formulation. Molecular docking studies have been performed to determine the combinatorial mode of action for the tablet formulation.Results: Friability and weight variation were less than 1% for each formulation, which were within range of prescribed pharmacopoeial recommendation. The hardness of 20 tablets showed 5-6.5Kg/cm2 for all formulations 5-6.5Kg/cm2. The optimized formulation resulted in 98% drug release after 28 h. The present study reports the synergistic effects of drug combination to inhibit cell growth in HepG2 cell line. Molecular docking studies showed that sorafenib has high binding affinity for B-Raf vascular endothelial growth factor receptor β and protein kinase B. Silibinin showed binding affinity with MAP kinase-11, protein phosphatase 2 A and tankyrase.Conclusion: The present study reports for the first time a novel formulation for sustained release and reduced toxicity of sorafenib with enhanced inhibitory effect of the drug combination on cancerous hepatic cell line as well collaborative mechanism of action for the formulation.

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