Melatonin in cancer treatment: Current knowledge and future opportunities
Authors : Wamidh H Talib, Ahmad Riyad Alsayed, Alaa Abuawad, Safa Daoud, Asma Ismail Mahmod
Abstract : Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.
Keywords : pineal gland; anticancer; cancer therapy; hormonal therapy; phytomelatonin
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Plant-derived natural products in cancer research: extraction, mechanism of action, and drug formulation
Authors : Wamidh H Talib, Izzeddin Alsalahat, Safa Daoud, Reem Fawaz Abutayeh, Asma Ismail Mahmod
Abstract : Cancer is one of the main causes of death globally and considered as a major challenge for the public health system. The high toxicity and the lack of selectivity of conventional anticancer therapies make the search for alternative treatments a priority. In this review, we describe the main plant-derived natural products used as anticancer agents. Natural sources, extraction methods, anticancer mechanisms, clinical studies, and pharmaceutical formulation are discussed in this review. Studies covered by this review should provide a solid foundation for researchers and physicians to enhance basic and clinical research on developing alternative anticancer therapies.
Keywords : alternative anticancer therapies; natural products; plant extracts; curcumin; thymoquinone
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Identification of potential COVID-19 main protease inhibitors using structure-based pharmacophore approach, molecular docking and repurposing studies
Authors : Safa Daoud, Shada J. Alabed, Lina A. Dahabiyeh
Abstract : The current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today’s diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.
Keywords : COVID-19, main protease, pharmacophore, structure-based modeling, docking study, remdesivir, repurposing
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Preparation, Physicochemical characterization and biological evaluation of some hesperidin metal complexes
Authors : Safa Daoud, Fatma U Afifi, Amal G Al-Bakri, Violet Kasabri, Imad I Hamdan
Abstract : The ability of hesperidin (HP) to form complexes with five metals; cobalt, nickel, zinc, calcium and magnesium was investigated. The complexation was studied using U.V spectroscopic titration, in methanol as well as aqueous buffer solutions (physiological conditions). Potential complexes were studied by IR and NMR spectroscopy, melting point and their solubility were also evaluated. The interaction of HP and its metal complexes with DNA was investigated by U.V spectroscopy. HP and its potential complexes were also tested for their ability to inhibit alpha amylase and alpha glucosidase enzymes. The results indicated that HP can form 1:1 complexes with cobalt, nickel and zinc in methanolic solution but not in aqueous buffers. Both HP and its metal complexes were found to intercalate DNA, at physiological condition, with preference to GC rich sequences. HP-metal complexes appeared to have higher affinity towards poly A DNA than the free HP. Neither HP nor its complexes exhibited antimicrobial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa or Candida albicans. Results showed that HP has little inhibitory action on glucosidase and amylase enzymes with no obvious effect of complexation on the behavior of free HP. In conclusion HP was shown to form 1:complexes with the studied metal in methanol but not in aqueous buffer solutions. In presence of DNA however, complex formation in aqueous solutions seem to be encouraged with differential effect between the complexes and free HP.
Keywords : Hesperidin, Chelation of polyphenols, Metals, Biological activity
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Pharmacophore modeling of JAK1: A target infested with activity-cliffs
Authors : Safa Daoud, Mutasem Taha
Abstract : Janus kinase 1 (JAK1) is protein kinase involved in autoimmune diseases (AIDs). JAK1 inhibitors have shown promising results in treating AIDs. JAK1 inhibitors are known to exhibit regions of SAR discontinuity or activity cliffs (ACs). ACs represent fundamental challenge to successful QSAR/pharmacophore modeling because QSAR modeling rely on the basic premise that activity is a smooth continuous function of structure. We propose that ACs exist because active ACs members exhibit subtle, albeit critical, enthalpic features absent from their inactive twins. In this context we compared the performances of two computational modeling workflows in extracting valid pharmacophores from 151 diverse JAK1 inhibitors that include ACs: QSAR-guided pharmacophore selection versus docking-based comparative intermolecular contacts analysis (db-CICA). The two methods were judged based on the receiver operating characteristic (ROC) curves of their corresponding pharmacophore models and their abilities to distinguish active members among established JAK1 ACs. db-CICA modeling significantly outperformed ligand-based pharmacophore modeling. The resulting optimal db-CICA pharmacophore was used as virtual search query to scan the National Cancer Institute (NCI) database for novel JAK1 inhibitory leads. The most active hit showed IC50 of 1.04 μM. This study proposes the use of db-CICA modeling as means to extract valid pharmacophores from SAR data infested with ACs.
Keywords : Activity cliffs QSAR JAK1 Pharmacophore dbCICA
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Determination of Antimicrobial Drug Resistance among Bacterial Isolates in Two Hospitals of Baghdad
Authors : Imad Shukur Mahmoud, Khalil Ibrahim Altaif, Mohammad Khaled Abu Sini, Safa Daoud, Nahla Numan Aqel
Abstract : Objective: To evaluate the resistance of clinical isolates from two main hospitals in Baghdad, Iraq, against commonly used antimicrobial drugs. Methods: Five hundred clinical samples were collected from various sources at two hospitals in Baghdad and subjected to establish microbiological methods to determine their sensitivity to commonly used antimicrobial drugs. The antimicrobial sensitivity test used was the Kirby-Bauer disc diffusion method. Interpretations of the test outcomes were according to international values. Results:Out of 500 clinical specimens, it was possible to obtain 239 bacterial isolates. The predominant isolates (74 specimens; 31%) were from throat swabs from which 40 isolates were of GAβHS followed by 16 of Klebsiella pneumoniae. The second group of isolates were from blood (67 specimens; 28%) in which Staphylococcus aureus was represented by 20 specimens followed by Proteus species by 16 specimens. The third group of isolates was from the urine specimens (42 specimens; 17.6%). The urine isolates were distributed as Proteus spp (20 specimens) followed by bacterial isolates of Pseudomonas aeruginosa and K. pneumoniae (8 specimens each). The fourth group of isolates was from sputum (40 specimens; 16.7%) in which GAβHS represented 18 isolates followed by 12 isolates of K. pneumoniae. No Proteus spp was isolated from either sputum or purulent wounds. Similarly, no GAβHS and K. pneumoniae were isolated from purulent wounds. The results of the antimicrobial resistance tests among the bacterial isolates revealed that all isolates were highly resistant to most of the drugs used in this study. GAβHS was resistant to all of the drugs except forCefotaxime (76.7%). Ps. aeruginosa isolates were completely resistant to Cefotaxime, Cephalexin and Amoxicillin. Conclusion: From this study it is concluded that multiple-resistant bacteria isolates are common and that antimicrobial resistance is widespread in Iraq. A policy to overcome this crisis will be urgently needed.
Keywords : Multi-Drug Resistance, Antimicrobial Agents, Antibiotic Sensitivity Test.
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Synthesis, computational, anticancerous and antiproliferative effects of some copper, manganese and zinc complexes with ligands derived from symmetrical 2,2’-diamino-4,4’-dimethyl-1,1’-biphenyl-salicylaldehyde
Authors : Taher S Ababneh, Mohammad El-Khateeb, Aissar K Tanash, Tareq Al-Shboul, Mohammad Jamal A Shammout, Taghreed Jazzazi, Mohammad Alomari, Safa Daoud, Wamidh H Talib
Abstract : Four new symmetrical Schiff bases derived from 2,2’-diamino-4,4’-dimethyl-1,1’-biphenyl-salicylaldehyde have been synthesized and characterized by elemental analysis and different spectroscopic techniques. The reaction of 2,2’-diamino-4,4’-dimethyl-1,1’-biphenyl with two equivalents of 5-tert-butyl-, 3,5-dinitro-, 3,5-dibromo- and 3-tert-butyl-salicylaldehyde yielded 2,2’-bis(5-tert-butyl-salicylideneamino)-4,4’-dimethyl-1,1’-biphenyl (A1) as well as the 3,5-dinitro- (A2), 3,5-dibromo- (A3) and 3-tert-butyl- (A4) substituted derivatives. The tetradentate ligands were then reacted with copper-, manganese- and zinc-acetate producing the tetra-coordinate metal complexes which were characterized by FTIR, UV-Visible spectroscopy, magnetic susceptibility and elemental analysis. Zinc complexes were characterized by 1H-NMR spectroscopy. Density functional theory (DFT) calculations at the B3LYP/6-31G(d) level of theory were carried out to fully optimize and examine the molecular geometries of complexes. Subsequently, IR vibrational and UV-Vis absorption spectra were computed and correlated with the observed values and the results are in good agreement with the experimental data. The anticancerous and antiproliferative activity of the A3 ligand and its metal complexes were determined.
Keywords : tetradentate schiff base, symmetrical metal complexes, DFT calculation, spectroscopy, anticancerous, antiproliferative
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Evaluation and molecular modelling of bis-Schiff base derivatives as potential leads for management of diabetes mellitus
Authors : Safa Daoud, Samar Thiab, Taghreed Jazzazi, Tareq Al-Shboul, Saeed Ullah
Abstract : Developing a medication to cure and manage diabetes mellitus complications is of interest in medicinal chemistry. Toward this end, six bis-biphenyl-salicylaldehyde Schiff base derivatives have been evaluated for their α-glucosidase inhibition, antiglycation and anti-inflammation potentials. Four compounds (compounds 2–5) showed an excellent α-glucosidase inhibitory effect superior to that produced by acarbose. Additionally, the docking study revealed that these compounds are anchored within the binding pocket of α-glucosidase via hydrogen bonding, π-stacking and hydrophobic interactions, comparable to a high number of hydrogen bonding involved in anchoring acarbose. Interestingly, all tested compounds showed varying degrees of antiglycation activity with superior activity for two of them (compound 1 and compound 6) compared to the standard rutin. Moreover, the results indicated an outstanding anti-inflammatory activity for two compounds (compounds 1 and 6) compared to ibuprofen.
Keywords : bis-Schiff bases, diabetes mellitus, glycation, postprandial hyperglycemia, α-glucosidase, docking study
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The first detection of Pneumocystis jirovecii in asthmatic patients post COVID-19 in Jordan
Authors : Ahmad Riyad Alsayed, Wamidh Talib, Abdullah Al-Dulaimi, Safa Daoud, Mohammed Al Maqbali
Abstract : Pneumocystis jirovecii pneumonia (PCP), caused by fungal species named Pneumocystis jirovecii, is a frequent opportunistic infection in those with human immunodeficiency virus (HIV) infection. However, PCP has been documented in immunocompetent patients. This study aims to determine if P. jirovecii detection occurs in asthma patients following coronavirus disease 2019 (COVID-19) in a Jordanian cohort. Also, to evaluate a method of TaqMan quantitative polymerase chain reaction (qPCR) assay to detect P. jirovecii, from sputum samples. The nasopharyngeal swabs were used to detect SARS-CoV-2 and sputum samples were tested for P. jirovecii using real time qPCR assay. Beta-tubulin (BT) and Dihydrofolate reductase (DHFR) genes were the directed targets of P. jirovecii. The results showed that the mean qPCR efficiencies of BT and DHFR were 96.37% and 100.13%, respectively. Three out of 31 included patients (9.7%) had a positive P. jirovecii. All of the three patients had used oral corticosteroids (OCS) in the last two months due asthma exacerbation and were treated with OCS for COVID-19. This is the first study based in Jordan to demonstrate that P. jirovecii and COVID-19 can co-exist and that it is important to maintain a broad differential diagnosis, especially in immunocompromised patients. Chronic lung disease can be a risk factor for the P. jirovecii colonization possibly due to corticosteroid's immunosuppression.
Keywords : Asthma, COVID-19, developing country, Pneumocystis jirovecii, polymerase chain reaction
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Ligand-Based Modeling of CXC Chemokine Receptor 4 and Identification of Inhibitors of Novel Chemotypes as Potential Leads towards New Anti-COVID-19 Treatments.
Authors: Safa Daoud, Mutasem Taha
Abstract : Background: Chemokines are involved in several human diseases and in different stages of COVID-19 infection and play critical role in the pathophysiology of the associated acute respiratory disease syndrome, a major complication leading to death among COVID-19 patients. In particular, CXC chemokine receptor 4 (CXCR4) was found to be highly expressed in COVID-19 patients. Methods: We herein describe a computational workflow based on combining pharmacophore modeling and QSAR analysis towards the discovery of novel CXCR4 inhibitors. Subsequent virtual screening identified two promising CXCR4 inhibitors from the National Cancer Institute (NCI) list of compounds. The most active hit showed in vitro IC50 value of 24.4 µM. Results and Conclusion: These results prove the validity of the QSAR model and associated pharmacophore models as means to screen virtual databases towards new CXCR4 inhibitors as leads for the development of new COVID-19 therapies.
Keywords : Coronavirus disease, CXCR4, pharmacophore modeling, QSAR, virtual screening, in vitro assay
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Discovery of new Cdc2-like kinase 4 (CLK4) inhibitors via pharmacophore exploration combined with flexible docking-based ligand/receptor contact fingerprints and machine learning
Authors : Mai Fayiz Al-Tawil, Safa Daoud, M Hatmal Ma'mon, Mutasem Omar Taha
Abstract : Cdc2-like kinase 4 (CLK4) inhibitors are of potential therapeutic value in many diseases particularly cancer. In this study, we combined extensive ligand-based pharmacophore exploration, ligand–receptor contact fingerprints generated by flexible docking, physicochemical descriptors and machine learning-quantitative structure–activity relationship (ML-QSAR) analysis to investigate the pharmacophoric/binding requirements for potent CLK4 antagonists. Several ML methods were attempted to tie these properties with anti-CLK4 bioactivities including multiple linear regression (MLR), random forests (RF), extreme gradient boosting (XGBoost), probabilistic neural network (PNN), and support vector regression (SVR). A genetic function algorithm (GFA) was combined with each method for feature selection. Eventually, GFA-SVR was found to produce the best self-consistent and predictive model. The model selected three pharmacophores, three ligand–receptor contacts and two physicochemical descriptors. The GFA-SVR model and associated pharmacophore models were used to screen the National Cancer Institute (NCI) structural database for novel CLK4 antagonists. Three potent hits were identified with the best one showing an anti-CLK4 IC50 value of 57 nM.
Keywords : CLK4, QSAR, pharmacophore
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Design and Synthesis of New JAK1 Inhibitors based on Sulfonamide-Triazine Conjugates
Authors : Safa Daoud, Mutasem O Taha
Abstract : Aims: Design of sulfonamide-triazine derivatives as JAK1 inhibitors. Background: JAK1 is a kinase involved in different autoimmune diseases. JAK1 inhibitors have shown promising results in treating autoimmune diseases. Objectives: To design new JAK1 inhibitors based on sulfonamides-triazine conjugates capable of binding interactions comparable to observed interactions anchoring potent crystallographic JAK1 inhibitors. Methods: The crystallographic structures of 4 diverse nanomolar inhibitors complexed within JAK1 were used to guide the synthesis of new diaminotriazine-sulfonamide-based JAK1 inhibitors. Results: Nineteen compounds have been prepared, some of which exhibited low micromolar IC50 values against JAK1. Conclusions: Crystallographic complexes of diverse JAK1 inhibitors were successfully used to guide the synthesis of novel sulfonamide-triazine-based low micromolar JAK1 inhibitors.
Keywords : JAK1 inhibitors; crystallographic complexes; diamino-triazines; docking; dose-response; sulfonamides
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