Browsing by Author "Uba, Abdullahi Ibrahim"

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Citation Count: 14
Antioxidant and Enzyme Inhibitory Properties, and HPLC-MS/MS Profiles of Different Extracts of Arabis carduchorum Boiss.: An Endemic Plant to Turkey
(Mdpi, 2022) Uba, Abdullahi Ibrahim; Zengin, Gokhan; Montesano, Domenico; Cakilcioglu, Ugur; Selvi, Selami; Ulusan, Musa Denizhan; Caprioli, Giovanni
In this study, six extracts of Arabis carduchorum prepared from solvents of varying polarity (water, methanol, ethyl acetate, dichloromethane, and n-hexane) were investigated for their chemical profiles and total phenolic and flavonoid contents (TPC/TFC) using HPLC-MS/MS and spectrophotometric/colorimetric assays, respectively, along with the assessment of their antioxidant and enzyme inhibitory effects. In general, the polar extracts (methanol, water, and infusion) showed higher TPC/TFC than the other extracts (range: 13.73-26.62 mg GAE/g; 2.66-52.95 mg RE/g, respectively). The total antioxidant capacity of the polar extracts ranged from 0.90-1.85 mmol TE/g in phosphomolybdenum assay, while the free radical scavenging potential ranged from 4.36-32.13 mg TE/g and 12.58-67.73 mg TE/g in DPPH and ABTS assays, respectively. While the water and infuse extract inhibited only butyrylcholinesterase (2.68 and 2.39 mg GALAE/g, respectively), the other extracts were found to inhibit both acetyl- and butyryl-cholinesterases (0.96-2.73 mg GALAE/g and 1.86-5.11 mg GALAE/g, respectively). On the contrary, all extracts exhibited anti-tyrosinase (40.24-59.22 mg KAE/g) and anti-amylase (0.09-0.63 mmol ACAE/g) activities. Overall, this study highlighted the effect of solvent polarity on the extraction of bioactive compounds and the biological properties of the extracts of A. carduchorum; hence, the results obtained could be used to guide optimum extraction in future studies.
Citation Count: 3
Bridging the Chemical Profiles and Biological Effects of Spathodea campanulata Extracts: A New Contribution on the Road from Natural Treasure to Pharmacy Shelves
(Mdpi, 2022) Swiatek, Lukasz; Sieniawska, Elwira; Sinan, Kouadio Ibrahime; Zengin, Gokhan; Uba, Abdullahi Ibrahim; Bene, Kouadio; Maciejewska-Turska, Magdalena
Spathodea campanulata is an important medicinal plant with traditional uses in the tropical zone. In the current work, we aimed to determine the chemical profiles and biological effects of extracts (methanolic and infusion (water)) from the leaves and stem bark of S. campanulata. The chemical components of the tested extracts were identified using LC-ESI-QTOF-MS. Biological effects were tested in terms of antioxidant (radical scavenging, reducing power, and metal chelating), enzyme inhibitory (cholinesterase, amylase, glucosidase, and tyrosinase), antineoplastic, and antiviral activities. Fifty-seven components were identified in the tested extracts, including iridoids, flavonoids, and phenolic acids as the main constituents. In general, the leaves-MeOH extract was the most active in the antioxidant assays (DPPH, ABTS, CUPRAC, FRAP, metal chelating, and phosphomolybdenum). Antineoplastic effects were tested in normal (VERO cell line) and cancer cell lines (FaDu, HeLa, and RKO). The leaf infusion, as well as the extracts obtained from stem bark, showed antineoplastic activity (CC50 119.03-222.07 mu g/mL). Antiviral effects were tested against HHV-1 and CVB3, and the leaf methanolic extract (500 mu g/mL) exerted antiviral activity towards HHV-1, inhibiting the viral-induced cytopathic effect and reducing the viral infectious titre by 5.11 log and viral load by 1.45 log. In addition, molecular docking was performed to understand the interactions between selected chemical components and viral targets (HSV-1 DNA polymerase, HSV-1 protease, and HSV-1 thymidine kinase). The results presented suggest that S. campanulata may be a bright spot in moving from natural sources to industrial applications, including novel drugs, cosmeceuticals, and nutraceuticals.
Citation Count: 18
Carboxylic acid derivatives display potential selectivity for human histone deacetylase 6: Structure-based virtual screening molecular docking and dynamics simulation studies
(Elsevier Science, 2018) Yelekçi, Kemal; Yelekçi, Kemal
Human histone deacetylase 6 (HDAC6) has been shown to play a major role in oncogenic cell transformation via deacetylation of alpha-tubulin making it a viable target of anticancer drug design and development. The crystal structure of HDAC6 catalytic domain 2 has been recently made available providing avenues for structure-based drug design campaign. Here in our continuous effort to identify potentially selective HDAC6 inhibitors structure-based virtual screening of similar to 72 461 compounds was carried out using Autodock Vina. The top 100 compounds with calculated Delta G < -10 kcal/mol were manually inspected for binding mode orientation. Furthermore the top 20 compounds with reasonable binding modes were evaluated for selectivity by further docking against HDAC6 and HDAC7 using Autodock4. Four compounds with a carboxylic fragment displayed potential selectivity for HDAC6 over HDAC7 and were found to have good druglike and ADMET properties. Their docking complexes were then submitted to 10 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software to examine the stability of ligand binding modes. These predicted inhibitors remained bound to HDAC6 in the presence of water and ions and the root-mean-square deviation (RMSD) radius of gyration (Rg) and nonbond distance (protein-ligand) profiles suggested that they might be stable over time of the simulation. This study may provide scaffolds for further lead optimization towards the design of HDAC6 inhibitors with improved selectivity. (C) 2018 Elsevier Ltd. All rights reserved.
Citation Count: 4
Chemical and Biological Investigations of Allium scorodoprasum L. Flower Extracts
(Mdpi, 2023) Dordevski, Nikoleta; Uba, Abdullahi Ibrahim; Zengin, Gokhan; Bozunovic, Jelena; Gasic, Uros; Ristanovic, Elizabeta; Ciric, Ana
This study was designed to investigate the impact of different extraction solvent systems on the chemical composition and biological activities of Allium scorodoprasum L. (Amaryllidaceae)-the medicinal plant that was traditionally used as a remedy in the medieval period in the Balkans. Targeted chemical analysis of nine different extracts was performed by UHPLC(-)HESI-QqQ-MS/MS. Antimicrobial and antibiofilm activities of the extracts were investigated on sixteen clinical isolates of bacteria, yeasts and dermatomycetes, all isolated from infected human skin and corneal formations. Cytotoxicity and wound-healing properties were tested on human immortalized keratinocytes (HaCaT cell line). Antioxidant activity was assessed by six different assays, while beneficial potential against certain neurodegenerative diseases and type 2 diabetes was determined in selected enzyme inhibition assays coupled with molecular modeling. The results showed that the obtained extracts were rich in phenolic compounds, especially flavonoid glycosides such as rutin and kaempferol 3-O-glucoside. All of the extracts showed antimicrobial, wound-healing, antioxidant and anti-enzymatic properties. This study is the first of its kind, linking the medieval medicinal use of wild-growing flowers of A. scorodoprasum with contemporary in vitro scientific approaches.
Citation Count: 1
Chemical profile, antiproliferative and antibacterial activities and docking studies of essential oil and hexane fraction of hydrosol from fresh leaf of Plectranthus amboinicus (Lour.) Spreng.
(Pergamon-Elsevier Science Ltd, 2023) Ibrahim, Enas I. E.; Yagi, Sakina; Tzanova, Tzvetomira; Schohn, Herve; Uba, Abdullahi Ibrahim; Zengin, Gokhan
Essential oils are commonly extracted from plants by hydrodistillation in which an aqueous phase called hydrosol is obtained. Like essential oil, this by-product of distillation can be a source of natural bioactive molecules with health benefits. This study aimed at the investigation of the chemical profile, antiproliferative and antibacterial activities of essential oil and hexane fraction of hydrosol from Plectrunthus amboinicus (family Lamiacease) fresh leaf cultivated in Sudan. Essential oil was obtained by hydrodistilation and hexane fraction (HF) was derived from hydrosol by liquid -liquid extraction. Results showed that the phenolic monoterpene thymol (72.9%) was the dominant component of the essential oil while the HF was characterized by the presence of long-chain (n-C29 to n-C68) alkanes (91.4%). The HF showed highest antiproliferative activity against the colon cancer HT29 (IC50 9.2 mu g/mL) and HCT116 (IC50 7.7 mu g/mL) cell lines. The essential oil exerted best antibacterial activity with highest inhibition (22.0-22.3 mm) and minimum inhibitory concentration (31 mu g/mL) against the Gram positive bacteria Bacillus subtilis and Staphylococcus aureus. In silico study showed that the major components of the oil displayed higher docking scores than those present in the HF suggesting an antagonistic effect by other molecules in the essential oil. In conclusion, beside the essential oil, the hydrosol possesses promising bioactive composition suggesting that it could be exploited for further therapeutic applications.
Citation Count: 6
The design of potent HIV-1 integrase inhibitors by a combined approach of structure-based virtual screening and molecular dynamics simulation
(Taylor & Francis Ltd, 2018) Yelekçi, Kemal; Yelekçi, Kemal; Uba, Abdullahi Ibrahim
Bu araştırmanın amacı, AIDS olarak bilinen insan bağışıklık sistemine etki eden, duraksamayan ve depresif bir hastalığa neden olan HIV-1'in tedavisi için potansiyel inhibitörleri elde etmektir. HIV-1 integraz inhibitörleri, HIV-1 enfeksiyonunun tedavisinde çok önemlidir. İntegraz enziminin (IN) inhibe edilmesi HIV-1 virüsünün çoğalma işleminin sonlandırılmasına neden olur. Böylece yaşam döngüsüne son verir. Bu inhibitörleri elde etmek için bilgisayar destekli in silico yaklaşım kullanılmıştır. Temelde, Otava Kimya Kütüphanesi tarandı ve inhibitör tasarımında kullanılan sistematik yaklaşımlar uygulandı, böylece dört güçlü integraz inhibitörü bulundu. İnhibitörlerin enzime bağlanma değerleri PyRx ve AutoDock 4.2 doklama programları kullanılarak gerçekleştirildi. Çalışmada bir kimyasalın güçlü bir inhibitör olabilmesi için hesaplanan serbest bağ enerjisi = -8.00 kcal / mol veya daha az olması ve integrazın aktif bölgesinde bulunan 3 önemli amino asidinden herhangi biri ile de etkileşimde bulunması kriterine uyulmuştur. Discovery Studio Visualizer, inhibitörlerin yapısını çizmekte, inhibitörü komplekslerinin resimlerini üretmekte, enzim ve inhibitör arasındaki etkileşimin türünü belirlememizi sağlayan 2D ve 3D yapıları görüntülemek için kullanıldı. Elde edilen dört güçlü inhibitörden, kendimizin tasarladığı moleküllerden (Ki= 652.83 nanomolar bir ve bağlanma serbest enerjisi -8.44kcal / mol), kalan üç inhibitörde, Otava Kimya Kütüphanesi'nde tarandı ve Otava koduyla parantez içerisinde listelenmiştir. Bunların inhibisyon sabiti ve bağlanma enerjileri sırasıyla; 107320240, Ki=131.7nm, -9.39kcal/ mol; 109750115, Ki= 44.19nm, -10.03kcal / mol; 111150115 Ki = 395.19nm, -8.74kcal / mol olarak bulunmuştur.
Citation Count: 14
Differential Metabolomic Fingerprinting of the Crude Extracts of Three Asteraceae Species with Assessment of Their In Vitro Antioxidant and Enzyme-Inhibitory Activities Supported by In Silico Investigations
(Mdpi, 2022) Zengin, Gokhan; Fahmy, Nouran M.; Sinan, Kouadio Ibrahime; Uba, Abdullahi Ibrahim; Bouyahya, Abdelhakim; Lorenzo, Jose M.; Yildiztugay, Evren
The Asteraceae is a large family, rich in ornamental, economical, and medicinally valuable plants. The current study involves the analytical and pharmacological assessment of the methanolic extracts of three less investigated Asteraceae plants, namely Echinops ritro, Centaurea deflexa, and Tripleurospermum decipiens, obtained by three different extraction methodologies viz. maceration (MAC), ultrasound-assisted extraction (UAE), and homogenizer-assisted extraction (HAE). LC-MS-MS analysis of E. ritro, C. deflexa, and T. decipiens extracts led to the identification of ca. 29, 20, and 33 metabolites, respectively, belonging to flavonoids, phenolic acids, and fatty acids/amides. Although there were significant differences in the quantitative metabolite profiles in the extracts of E. ritro and T. decipiens based on the used extraction method, no significant variation was observed in the extracts of C. deflexa in the three implemented extraction techniques. The antioxidant activities of the nine extracts were assessed in vitro using six different assays viz. DPPH, ABTS, CUPRAC, FRAP, PDA, and metal chelation assay (MCA). The HAE/UAE extracts of E. ritro and the UAE/ MAC extracts of C. deflexa displayed the highest antioxidant activity in the DPPH assay, while the UAE extract of T. decipiens showed the strongest antioxidant activity in both the CUPRAC and MCA assays. The enzyme inhibitory activities of the nine extracts were studied in vitro on five different enzymes viz. tyrosinase, alpha-amylase, alpha-glucosidase, acetylcholinesterase (AChE), and butyrylcholinestrase (BChE), affecting various pathological diseases. Concerning C. deflexa, its MAC /UAE extracts showed the strongest inhibition on alpha-amylase, while its UAE/HAE extracts displayed strong inhibitory power on AChE. However, no significant difference was observed on their effects on tyrosinase or BChE. For T. decipiens, its UAE/HAE showed potent inhibition to alpha-glucosidase, MAC/ HAE significantly inhibited AChE and BChE, while UAE could strongly inhibit tyrosinase enzyme. For E. ritro, all extracts equally inhibited alpha-amylase and alpha-glucosidase, MAC/HAE strongly affected tyrosinase, HAE/MAC best inhibited BChE, while HAE inhibited AChE to a greater extent. Chemometric analysis using PCA plot was able to discriminate between the plant samples and between the implemented extraction modes. The in vitro enzyme inhibitory activities of the extracts were supported by in silico data, where metabolites, such as the lignan arctiin and the flavonoid vicenin-2, dominating the extract of C. deflexa, displayed strong binding to AChE. Similarly, chlorogenic and dicaffeoyl quinic acids, which are some of the major metabolites in the extracts of E. ritro and T. decipiens, bound with high affinity to alpha-glucosidase.
Citation Count: 6
Evaluating the phyto-complexity and poly-pharmacology of spices: The case of Aframomum melegueta K. Schum (Zingiberaceae)
(Elsevier, 2022) Luca, Simon Vlad; Trifan, Adriana; Zengin, Gokhan; Sinan, Kouadio Ibrahim; Uba, Abdullahi Ibrahim; Korona-Glowniak, Izabela; Skalicka-Wozniak, Krystyna
The seeds of Aframomum melegueta K. Schum (grains of paradise, Zingiberaceae) are used as a common spice in African countries and a fine condiment in the European cuisine. In this study, we evaluated the phytochemical profile of various seed extracts of A. melegueta as well as their antimicrobial, antioxidant and enzyme inhibitory effects. In total, 25 diarylheptanoids, five gingerol derivatives and nine phenolic/organic acids were tentatively annotated in A. melegueta by liquid chromatography hyphenated with high resolution tandem mass spectrometry (LC-HRMS/MS). A. melegueta showed a moderate inhibitory activity against different human pathogenic mi-crobial strains, with H. pylori the most sensitive microorganism. A strong antioxidant and enzyme inhibitory potential was shown in various radical scavenging, reducing and chelating assays as well as in cholinesterase, tyrosinase and glucosidase assays. Several specialized metabolites from A. melegueta (diarylheptanoids, ginger-ols) were shown to be directly linked with the investigated antioxidant and enzyme inhibitory activities, as evaluated through the correlation analysis. In addition, two diarylheptanoids (one heptan-3-ol and one heptan-3,5-diol) displayed the strongest binding to acetylcholinesterase (AChE) via multiple H-bonds, a couple of 7C-7C interactions and van der Waals interactions all over the catalytic channel of the enzyme, as evidenced by the molecular docking study. Overall, our work brings new contributions to the phyto-complexity and poly -pharmacology of spices from genus Aframomum than can find future applications in pharmaceutical, nutraceu-tical or cosmeceutical industry.
Citation Count: 2
Evaluation of the Potential Therapeutic Properties of Liquidambar orientalis Oil
(Wiley-v C H verlag Gmbh, 2023) Baloglu, Mehmet Cengiz; Yildiz Ozer, Lutfiye; Pirci, Buket; Zengin, Gokhan; Uba, Abdullahi Ibrahim; Altunoglu, Yasemin Celik
Liquidambar orientalis Mill., commonly called the Anatolian sweetgum or Sigla tree, is endemic to southwestern Turkey. It has been historically significant in traditional medicine. In our research, we delved into the therapeutic attributes of its oil, emphasizing its antioxidant, antimicrobial, and antitumor properties. The primary chemical constituent of the gum is styrene, accounting for 78.5 %. The gum demonstrated antioxidant capabilities in several assays, including in 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2 '-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), cupric reducing antioxidant capacity (CUPRAC) and ferric reducing antioxidant power (FRAP). It displayed bactericidal actions against various gram-positive bacteria, such as Staphylococcus aureus, and gram-negative strains, including Escherichia coli. Additionally, the oil showcased potent antitumor effects against breast (MDA-MB-231), lung (A549), and prostate (PC3) cancer cell lines. These effects were found to be both time- and dose-dependent. L. orientalis Mill. oil showed the best antitumor activity against breast, lung, and prostate cancer cell lines after the 24 h and 48 h treatment. Its oil might induce autophagy in the PC3 prostate cancer cell line, whereas its cytotoxicity against MDA-MB-231 and A549 cancer cell lines might not be correlated with autophagy or apoptosis pathways. In conclusion, the oil from the Sigla tree offers promising therapeutic potential and warrants further exploration.
Citation Count: 12
Examining the stability of binding modes of the co-crystallized inhibitors of human HDAC8 by molecular dynamics simulation
(Taylor & Francis Inc, 2019) Yelekçi, Kemal; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; Yelekçi, Kemal
Histone deacetylase (HDAC) 8 has been implicated as a potential therapeutic target in a variety of cancers neurodegenerative disorders metabolic dysregulation and autoimmune and inflammatory diseases. Several nonselective HDAC inhibitors have been co-crystallized with HDAC8. Molecular dynamics (MD) studies may yield valuable information on the structural stabilities of the complexes over time as determined by various pharmacophore features of the co-crystallized inhibitors. Here using 11 unmodified X-ray crystal structures of human HDAC8 (complexes) structure-based pharmacophore models were built and clustered based on distance - a function of the number of common pharmacophore features and the root-mean-squared displacement between the matching features. Based on this information a total of seven complexes (1T64 1W22 3RQD 3SFF 3F0R 5VI6 and 5FCW) were submitted to unrestrained 50 ns-MD simulations using nanoscale MD (NAMD) software. 1T64 (HDAC8 in complex with TSA) was found to show the highest stability over time presumably because of the TSA's ability to span HDAC8 catalytic channel and form a strong ionic interaction with zinc metal ion. Other stable complexes were 1W22 3SFF 3F0R and 5FCW. However 3RQD and 5VI6 showed relative instability over 50 ns time period. This may be attributed to bulkiness of the capping groups of both largazole thiol and trapoxin A making them unable to fit well into the active site of HDAC8. They rather formed steric clashes with residues on loop regions near the entrance to the channel. Thus 1T64 and similar crystal structures may be good candidates for HDAC8 structural dynamics studies and inhibitor design. Communicated by Ramaswamy H. Sarma
Citation Count: 7
Gathering scientific evidence for a new bioactive natural ingredient: The combination between chemical profiles and biological activities of Flueggea virosa extracts
(Elsevier, 2022) Zengin, Gokhan; Acqua, Stefano Dall'; Sinan, Kouadio Ibrahime; Uba, Abdullahi Ibrahim; Sut, Stefania; Peron, Gregorio; Etienne, Ouattara Katinan
Flueggea virosa (Roxb. ex Willd.) Royle is a plant with several traditional uses in tropical countries. To study the potential usefulness, extracts from stem barks and leaves of F. virosa were obtained with different solvents. The phytochemical composition was assessed using LC-MS and NMR. Triterpenes, as oleanolic (0.05-88.09 mg/g extract), and ursolic (0.03-94.36 mg/g extract) acids were determined. In addition, ellagic and gallic acid de-rivatives were present in large concentrations in some of the extracts. Antioxidant (radical scavenging, reduction ability, and metal chelating) and enzyme inhibitory (cholinesterase, tyrosinase, amylase, and glucosidase) effects were assessed by in vitro chemical assays. The methanol extracts and infusions from both parts show higher antioxidant ability when compared with ethyl acetate extracts, and the antioxidant capacity was correlated with the total phenolic contents of the tested extracts. The extracts demonstrate enzyme inhibitory abilities on AChE and BChE, and multivariate approaches allowed for correlating the activities with the presence of triterpenoids (R > 0.8). Furthermore, molecular docking was used to get insights into the interactions between the triterpe-noids and the tested enzymes. Together, these results indicate that F. virosa represents a significant source of naturally-occurring bioactive compounds that can be exploited as a new ingredient for the development of novel functional products with promising biological properties.
Citation Count: 25
Homology modeling of human histone deacetylase 10 and design of potential selective inhibitors
(Taylor & Francis Inc, 2019) Yelekçi, Kemal; Yelekçi, Kemal
Histone deacetylases (HDACs) are implicated in the pathology of various cancers, and their pharmacological blockade has proven to be promising in reversing the malignant phenotypes. However, lack of crystal structures of some of the human HDAC isoforms (e.g., HDAC10) hinders the design of the isoform-selective inhibitor. Here, the recently solved X-ray crystal structure of Danio rerio (zebrafish) HDAC10 (Protein Data Bank (PDB) ID; 5TD7, released on 24 May 2017) was retrieved from the PDB and used as a template structure to model the three-dimensional structure of human HDAC10. The overall quality of the best model (M0017) was assessed by computing its z-score-a measure of the deviation of the total energy of the structure with respect to an energy distribution derived from random conformations and by docking of known HDAC10 inhibitors to its catalytic cavity. Furthermore, to identify potential HDAC10-selective inhibitor ligand-based virtual screening was carried out against the ZINC database. The free modeled structure of HDAC10 and its complexes with quisinostat and the highest-ranked compound ZINC19749069 were submitted to molecular dynamics simulation. The comparative analysis of root-mean-squared deviation, root-mean-squared fluctuation, radius of gyration (Rg), and potential energy of these systems showed that HDAC10-ZINC19749069 complex remained the most stable over time. Thus, M0017 could be potentially used for structure-based inhibitor against HDAC10, and ZINC19749069 may provide a scaffold for further optimization. Communicated by Ramaswamy H. Sarma
Citation Count: 14
Identification of potential inhibitors of human methionine aminopeptidase (type II) for cancer therapy: Structure-based virtual screening, ADMET prediction and molecular dynamics studies
(Elsevier, 2020) Yelekçi, Kemal; Uba, Abdullahi Ibrahim; Keskin, Özlem; Gürsoy, Attila; Yelekçi, Kemal
Methionine Aminopeptidases MetAPs are divalent-cofactor dependent enzymes that are responsible for the cleavage of the initiator Methionine from the nascent polypeptides. MetAPs are classified into two isoforms: namely, MetAP1 and MetAP2. Several studies have revealed that MetAP2 is upregulated in various cancers, and its inhibition has shown to suppress abnormal or excessive blood vessel formation and tumor growth in model organisms. Clinical studies show that the natural product fumagillin, and its analogs are potential inhibitors of MetAP2. However, due to their poor pharmacokinetic properties and neurotoxicities in clinical studies, their further developments have received a great setback. Here, we apply structure-based virtual screening and molecular dynamics methods to identify a new class of potential inhibitors for MetAP2. We screened Otava's Chemical Library, which consists of about 3 200 000 tangible-chemical compounds, and meticulously selected the top 10 of these compounds based on their inhibitory potentials against MetAP2. The top hit compounds subjected to ADMET predictor using 3 independent ADMET prediction programs, were found to be drug-like. To examine the stability of ligand binding mode, and efficacy, the unbound form of MetAP2, its complexes with fumagillin, spiroepoxytriazole, and the best promising compounds compound-3369841 and compound-3368818 were submitted to 100 ns molecular dynamics simulation. Like fumagillin, spiroepoxytriazole, and both compound-3369841 and compound-3368818 showed stable binding mode over time during the simulations. Taken together, these uninherited-fumagillin compounds may serve as new class of inhibitors or provide scaffolds for further optimization towards the design of more potent MetAP2 inhibitors -development of such inhibitors would be essential strategy against various cancer types.
Citation Count: 11
An In-Depth Study on the Metabolite Profile and Biological Properties of Primula auriculata Extracts: A Fascinating Sparkle on the Way from Nature to Functional Applications
(Mdpi, 2022) Kurt-Celep, Inci; Zheleva-Dimitrova, Dimitrina; Gevrenova, Reneta; Uba, Abdullahi Ibrahim; Zengin, Gokhan; Yildiztugay, Evren; Picot-Allain, Carene Marie Nancy
The biological activity of the aerial part and rhizomes of Primula auriculata were assessed for the first time. The biological activities (antioxidant properties, enzyme inhibition, and AGE inhibition) as well as the phenolic and flavonoid contents of the ethyl acetate, ethanol, hydro-ethanol and water extracts of P. auriculata aerial parts and rhizomes were determined. Cell viability assays and gelatin zymography were also performed for MMP-2/-9 to determine the molecular mechanisms of action. The gene expression for MMPs was described with RT-PCR. The levels of various proteins, including phospho-Nf-kappa B, BCL-2, BAX, p-53, and cyclin D1 as well as RAGE were measured using Western blot analysis. The hydro-ethanol extract of the aerial part possessed the highest phenolic (56.81 mg GAE/g) and flavonoid (63.92 mg RE/g) contents. In-depth profiling of the specialized metabolites by ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) allowed for the identification and annotation of 65 compounds, including phenolic acids and glycosides, flavones, flavonols, chalcones, dihydrochalcones, and saponins. The hydro-ethanol extract of the aerial parts (132.65, 180.87, 172.46, and 108.37 mg TE/g, for the DPPH, ABTS, CUPRAC, and FRAP assays, respectively) and the ethanol extract of the rhizomes (415.06, 638.30, 477.77, and 301.02 mg TE/g, for the DPPH, ABTS, CUPRAC, and FRAP assays, respectively) exhibited the highest free radical scavenging and reducing activities. The ethanol and hydro-ethanol extracts of both the P. auriculata aerial part and rhizomes exhibited higher inhibitory activity against acetylcholinesterase, while the hydro-ethanol extracts (1.16 mmol ACAE/g, for both the aerial part and rhizomes extracts) were more active in the inhibition of alpha-glucosidase. After the treatment of an HT-29 colorectal cancer cell line with the extracts, the apoptosis mechanism was initiated, the integrity of the ECM was remodeled, and cell proliferation was also taken under control. In this way, Primula extracts were shown to be potential drug sources in the treatment of colorectal cancer. They were also detected as natural MMP inhibitors. The findings presented in the present study appraise the bioactivity of P. auriculata, an understudied species. Additional assessment is required to evaluate the cytotoxicity of P. auriculata as well as its activity in ex vivo systems.
Citation Count: 8
Integration of in vitro and in silico approaches to assess three Astragalus species from Turkey flora: A novel spotlight from lab bench to functional applications
(Elsevier, 2022) Zengin, Gokhan; Uba, Abdullahi Ibrahim; Ocal, Mustafa; Sharifi-Rad, Majid; Caprioli, Giovanni; Angeloni, Simone; Altunoglu, Yasemin Celik
Members of the genus Astragalus have a great interest as a source of natural bioactive compounds on a scientific platform. To provide multidirectional insights into three Astragalus species (A. setulosus, A. anthylloides, and A. ovalis), the current work focused on the chemical characterization and biological properties of their extracts (aerial parts and roots). The chemical characterization of the extracts was detected by HPLC-MS/MS analysis. The biological properties were evaluated by antioxidant, enzyme inhibitory, and cytotoxic parameters. Assays for radical quenching, reducing capacity, and metal chelation were also used to evaluate antioxidant properties. To test the enzyme inhibitory effects of the extracts, cholinesterases, tyrosinase, alpha-amylase, and alpha-glucosidase were utilized as target enzymes. Two cancer cell lines, (MCF-7 (human breast cancer cell line) and HeLa (Human cervix cancer cell line), were selected to evaluate cytotoxic effects. Generally, 5- caffeoylquinic acid (2.43-283.92 mu g/g extract), hyperoside (4.33-216.22 mu g/g extract) and rutin (1.09-184.98 mu g/g extract) were the main constituents. The extracts from aerial parts and roots of A. anthylloides showed stronger radical scavenging and reducing power abilities compared to A. setulosus and A. ovalis. The best AChE and BChE inhibitory effects were determined in the aerial parts of A. setulosus (2.18 mg GALAE/g) and mots of A. ovalis (4.76 mg GALAE/g), respectively. The extracts of A. ovalis had the highest tyrosinase inhibitory abilities. The extract from aerial parts of A. setulosus showed stronger cytotoxic effects compared to other extracts. Pearson's correlation analysis revealed that the presence of some compounds (resveratrol, p-coumaric, 5-caffeoylquinic, and ferulic acids, etc) was linked to the observed biological activities. Molecular docking was also provided for the possible interaction of enzymes as well as protein targets of the tested cell lines. Our findings provide a scientific basis for the Astragalus species, which may serve as a source of naturally occurring bioactive compounds for health-promoting applications.
Citation Count: 0
Intermolecular interactions in human HDAC8 crystal structures and the stability of binding modes of co-crystallized inhibitors
(Amer Chemical Soc, 2019) Yelekçi, Kemal; Uba, Abdullahi Ibrahim
[Abstract Not Available]
Citation Count: 16
Pharmacophore-based virtual screening for identification of potential selective inhibitors of human histone deacetylase 6
(Elsevier Sci Ltd, 2018) Yelekçi, Kemal; Yelekçi, Kemal
Histone deacetylase (HDAC) 6 plays a role in oncogenic transformation and cancer metastasis via tubulin deacetylation, making it a critical target for anticancer drug design. However, lack of selectivity shown by many of the current HDAC6 inhibitors in clinical use and trials prompts the continuous search for selective inhibitors. Here, 10 pharmacophore hypotheses were developed based on the 3D common features of training set of 20 HDAC inhibitors in clinical use and trials. The hypotheses were validated using a test set of another 20 HDAC inhibitors along with 400 inactive (decoys) molecules based on Giiner-Henry pharmacophore scoring method. Hypothesis 1 consisting of 1 H-bond donor, 1 H-bond acceptor and 2 hydrophobic features, was used to screen "DruglikeDiverse" database using Biovia Discovery Studio 4.5. The top 10 hit compounds were selected based on the pharmacophore fit values ( > 3.00). Their binding affinity against HDAC6 compared to class I HDACs (1, 2, 3 & 8) and a class IIa member (HDAC7), was calculated by molecular docking using AutoDock4. The stability of binding modes of 2 potential HDAC6-selective inhibitors (ENA501965 and IBS399024) was examined by 30 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software. Both ligands showed potential stability in HDAC6 active site over time. Therefore, these may provide additional scaffolds for further optimization towards the design of safe, potent and selective HDAC6 inhibitors.
Citation Count: 18
Phenolic Profile, Antioxidant and Enzyme Inhibitory Activities of Leaves from Two Cassia and Two Senna Species
(Mdpi, 2022) Omer, Haifa A. A.; Caprioli, Giovanni; Abouelenein, Doaa; Mustafa, Ahmed M.; Uba, Abdullahi Ibrahim; Ak, Gunes; Ozturk, Refiye Beyza
Several species within the genera Cassia or Senna have a treasure of traditional medicines worldwide and can be a promising source of bioactive molecules. The objective of the present study was to evaluate the phenolic content and antioxidant and enzyme inhibition activities of leaf methanolic extracts of C. fistula L., C. grandis L., S. alexandrina Mill., and S. italica Mill. The two Cassia spp. contained higher total polyphenolic content (42.23-49.75 mg GAE/g) than the two Senna spp., and C. fistula had significantly (p < 0.05) the highest concentration. On the other hand, the Senna spp. showed higher total flavonoid content (41.47-59.24 mg rutin equivalent per g of extract) than that found in the two Cassia spp., and S. alexandrina significantly (p < 0.05) accumulated the highest amount. HPLC-MS/MS analysis of 38 selected bioactive compounds showed that the majority of compounds were identified in the four species, but with sharp variations in their concentrations. C. fistula was dominated by epicatechin (8928.75 mu g/g), C. grandis by kaempferol-3-glucoside (47,360.04 mu g/g), while rutin was the major compound in S. italica (17,285.02 mu g/g) and S. alexandrina (6381.85). The methanolic extracts of the two Cassia species exerted significantly (p < 0.05) higher antiradical activity, metal reducing capacity, and total antioxidant activity than that recorded from the two Senna species' methanolic extracts, and C. fistula displayed significantly (p < 0.05) the highest values. C. grandis significantly (p < 0.05) exhibited the highest metal chelating power. The results of the enzyme inhibition activity showed that the four species possessed anti-AChE activity, and the highest value, but not significantly (p >= 0.05) different from those obtained by the two Cassia spp., was exerted by S. alexandrina. The Cassia spp. exhibited significantly (p < 0.05) higher anti-BChE and anti-Tyr properties than the Senna spp., and C. grandise revealed significantly (p < 0.05) the highest values. C. grandise revealed significantly (p < 0.05) the highest alpha- amylase inhibition, while the four species had more or less the same effect against the alpha-glucosidase enzyme. Multivariate analysis and in silico studies showed that many of the identified phenols may play key roles as antioxidant and enzyme inhibitory properties. Thus, these Cassia and Senna species could be a promising source of natural bioactive agents with beneficial effects for human health.
Citation Count: 5
Status of malondialdehyde, catalase and superoxide dismutase levels/activities in schoolchildren with iron deficiency and iron-deficiency anemia of Kashere and its environs in Gombe State, Nigeria
(Elsevier, 2019) Usman, Sani Sharif; Dahiru, Musa; Abdullahir, Bashir; Abdullahir, Shariff Bilal; Maigari, Usman Muhammad; Uba, Abdullahi Ibrahim
Background: Iron-deficiency anemia (IDA) or iron deficiency (ID) is by far the most common form of disorder affecting the cognitive development, physical growth and school performance of children in developing countries including Nigeria. Objectives: In the present study, we aimed to examine whether IDA or ID, or both are associated with oxidative stress or otherwise by assessing the perturbations in oxidative stress markers including malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD). Methods: Here, a total of eighty-one IDA, ID, and healthy control subjects of twenty-seven replicates each, were recruited and investigated. Human serum MDA, CAT and SOD levels were quantitatively analyzed using Enzyme-Linked Immunosorbant Assay. Results: Mean serum MDA levels of IDA (5.10 +/- 2.35 mmol/L) and ID (4.05 +/- 1.35 mmol/L) groups were found to perturb significantly (p < 0.05), being higher than those of control (3.30 +/- 0.95 mmol/L) subjects. Similarly, mean serum MDA levels of IDA (5.10 +/- 2.35 mmol/L) group was found to be significantly (p < 0.05) higher when compared with ID (4.05 +/- 1.35 mmol/L) subjects. Conversely, mean serum CAT and SOD activities of IDA (8.35 +/- 2.21 ng/mL and 340.70 +/- 153.65 ng/mL) group were found to differ significantly (p < 0.05), and those of ID (9.40 +/- 1.47 ng/mL and 435.00 +/- 144.75 ng/mL) subjects were found to perturb slightly (p > 0.05), being lower than those of control (10.40 +/- 4.31 ng/mL and 482.12 +/- 258.37 ng/mL) subjects. Conclusions: Taken together, the results of the present study showed that lipid peroxidation was dramatically increased in both IDA and ID subjects in hydroperoxide-superoxide-dependent manner; in contrast, enzymatic antioxidant capacity was drastically decreased in both IDA and ID groups as evidenced by biochemical markers.
Citation Count: 20
Synthesis, molecular modeling, in vivo study and anticancer activity against prostate cancer of (+) (S)-naproxen derivatives
(Elsevier Masson s.r.l., 2020) Yelekçi, Kemal; Karasulu, Hatice Yeşim; Karasulu, Ercüment; Birgül, Kaan; Yıldırım, Yeliz; Bekçi, Hatice; Cumaoğlu, Ahmet; Yılmaz, Özgür; Kabasakal, Levent; Küçükgüzel, Şükriye Güniz; Yelekçi, Kemal
In this study, (S)-naproxen thiosemicarbazides (3a-d), 1,2,4-triazoles (4a-c), triazole-thioether hybride compounds (5a-p) were synthesized and their structures (3a, 3d, 4a and 5a-p) were confirmed by FT-IR, 1H NMR,13C NMR, HR-Mass spectra and elemental analysis. These compounds are designed to inhibit methionine amino peptidase-2 (MetAP2) enzyme in prostate cancer. These compounds (3d, 5a-p) evaluated against androgen-independent prostate adenocarcinoma (PC-3, DU-145) and androgen-dependent prostate adenocarcinoma (LNCaP) cell lines by using MTS method. Compounds 5a, 5b, 5d and 5e showed 14.2, 5.8, 10.8 and 8.4 μM anticancer activity against PC-3 cell lines, compounds 5e, 5g and 5n presented anticancer activity against DU-145 cell lines 18.8, 12.25 and 10.2 μM, and compounds 5g, 5m and 5n exhibited anticancer activity against LNCaP cell lines 12.25, 22.76 and 2.21 μM, respectively. Consequently, of these results, compounds 5e and 5n showed the highest activities against androgen dependent and independent prostate cancer cell lines, so these compounds could be potent small molecules against prostate cancer. Furthermore, mitogen-activated protein kinase (MAPK) pathway activation, AKT (protein kinase B) phosphorylation and androgen receptor activation of compound 5n (SGK636) were investigated in LNCaP cells by using Western blot method. Compound 5n (SGK636) was also tested against mRNA expression analysis of the Bax, Bcl-2, Caspase 3, Caspase 9 by using real-time PCR analysis. Compound 5n was given to nude male mice with cancer in comparison to the control group. Compound 5n was found to reverse the malignant phenotype in the nude male mice, whereas the prostate cancer progressed in the control group. Analysis of some blood parameters in the study showed that they were within the normal values with respect to the control. The blood values of the animals treated according to the control group also exhibited compliance with the blood limit values. Molecular docking and dynamics simulation of compound 5n binding to Methionine Aminopeptidase 2 (MetAP2) enzyme rationalized its potential activity. In addition, inhibition assay MetAP2 enzyme of compound 5n was evaluated. Taken together, we suggest compound 5n to be a potential candidate for prostate cancer therapy.