Computational fragment-based drug design of potential Glo-I inhibitors.

In this study, a fragment-based drug design approach, particularly de novo drug design, was implemented utilising three different crystal structures in order to discover new privileged scaffolds against glyoxalase-I enzyme as anticancer agents. The fragments were evoluted to indicate potential inhibitors with high receptor affinities. The resulting compounds were served as a benchmark for choosing similar compounds from the ASINEX® database by applying different computational ligand-based drug design techniques. Afterwards, the selection of potential hits was further aided by various structure-based approaches. Then, 14 compounds were purchased, and tested in vitro against Glo-I enzyme. Of the tested 14 hits, the biological screening results showed humble activities where the percentage of Glo-I inhibition ranged from 0-18.70 %. Compound 19 and compound 28, whose percentage of inhibitions are 18.70 and 15.80%, respectively, can be considered as hits that need further optimisation in order to be converted into lead-like compounds.

Lead optimization and biological evaluation of diazenylbenzenesulfonamides inhibitors against glyoxalase-I enzyme as potential anticancer agents.

In a previous report, we described the discovery of (E)-5-((8-hydroxyquinolin-5-yl)diazenyl)-2-methylbenzenesulfonamide as a potent inhibitor of GLO-I enzyme with IC50 of 1.28 ± 0.12 µM. Herein, lead optimization of this compound was achieved through targeting the central zinc atom and hydrophilic amino acid residues in the active site of the enzyme. Among the synthesized compounds, compound TS010 showed the most potent inhibitory activity with IC50 of 0.57 ± 0.04 µM. Compound TS013 also showed comparable activity to that of the lead compound with IC50 of 1.14 ± 0.03 µM. Molecular docking studies disclosed the binding mode of the compounds inside the active side of GLO-I enzyme.

Marine-Based Candidates as Potential RSK1 Inhibitors: A Computational Study.

Manzamines are chemically related compounds extracted from the methanolic extract of Acanthostrongylophora ingens species. Seven compounds were identified by our research group and are being characterized. As their biological target is unknown, this work is based on previous screening work performed by Mayer et al., who revealed that manzamine A could be an inhibitor of RSK1 kinase. Within this work, the RSK1 N-terminal kinase domain is exploited as a target for our work and the seven compounds are docked using Autodock Vina software. The results show that one of the most active compounds, Manzamine A N-oxide (5), with an IC50 = 3.1 µM, displayed the highest docking score. In addition, the compounds with docking scores lower than the co-crystalized ligand AMP-PCP (-7.5 and -8.0 kcal/mol) for ircinial E (1) and nakadomarin A (7) were found to be inferior in activity in the biological assay. The docking results successfully managed to predict the activities of four compounds, and their in silico results were in concordance with their biological data. The ß-carboline ring showed noticeable receptor binding, which could explain its reported biological activities, while the lipophilic side of the compound was found to fit well inside the hydrophobic active site.

The ethics of practicing defensive medicine in Jordan: a diagnostic study.

BACKGROUND: Defensive medicine (DM) practice refers to the ordering or prescription of unnecessary treatments or tests while avoiding risky procedures for critically ill patients with the aim to alleviate the physician's legal responsibility and preserve reputation. Although DM practice is recognized, its dimensions are still uncertain. The subject has been highly investigated in developed countries, but unfortunately, many developing countries are unable to investigate it properly. DM has many serious ramifications, exemplified by the increase in treatment costs for patients and health systems, patients' exposure to risks, and negative effects on the psychological health of both health providers and recipients. Ultimately, the most serious consequence is the ethical consequences. METHODS: This work is based on a review of the literature related to DM worldwide and a comparison with the available knowledge found in Jordan. It is qualitative with a descriptive nature, aiming to diagnose the current DM practice in Jordan. RESULTS: This is the first published article that discusses DM in Jordan by diagnosing its ethical and economic consequences for the health system as well as for patients. Despite the knowledge of the reasons that support its practice, little is being done to solve this issue. The absence of agreeable medical malpractice law, the dearth of unified medical protocols, the overwhelming pressure imposed by patients on medical staff, and the deteriorating patient-physician relationship are some of the causes of DM practice. Surely, the solution to these issues is to focus on fortifying the ethical and humanitarian aspects on the side of both the physician and the patient to ensure positive collaboration. The ethical aim of the physician to treat the patient faithfully and do what is possible to help combined with the appreciation of the physician's efforts and the choice to not take advantage of the physician through litigation could be the most reasonable solution in the near future. CONCLUSION: Jordan is suffering from DM due to the limited financial expenditure on the health sector and the impracticality of medical malpractice law. The authors highlight that the cardinal step in solving this dilemma is restoring the ethical dimension of the patient-physician relationship.

An Ethical Roadmap for Prioritizing Medical Resources Within Muslim Societies During the COVID-19 Pandemic.

Profound ethical challenges have been generated by the emergence of the COVID-19 pandemic. The unprecedented plights that have arisen have led nations to devise ethical roadmaps for handling their finite resources. Muslim countries are no exception and must continue to endure the effects of the pandemic, as more waves of infections from new strains are being reported. Given the scarcity of resources available to some countries, it is critical to adopt a roadmap to prioritize these limited resources based on ethical guidelines that are acceptable to Muslim communities. This work describes the concept of "ijtihad", a process frequently used by Muslim scholars to develop novel solutions to deal with unprecedented events, such as the recent pandemic. In this manuscript, Islamic perspectives were discussed on social justice and equality and how limited resources can be used in a way consistent with such perspectives. Relying on previous experiences of the Muslim community, such as the plague of Amwas, in which social distancing and quarantine strategies were used effectively to control the disease, and utilizing available guidelines such as "Al-Qawaid Al-Fiqhiyyah" and "Fiqh Al-Nawazel", we propose a practical protocol and roadmap that can be applied in the current crisis. Managing and prioritizing limited medical resources requires a just and ethically acceptable system. Islamic leaders should immediately develop a roadmap that emphasizes ethical values such as ihsan and altruism to help Muslim countries prioritize the limited medical resources available to medical staff to guarantee the sustainability of health services.

Design, synthesis and biological evaluation of novel glyoxalase I inhibitors possessing diazenylbenzenesulfonamide moiety as potential anticancer agents.

The enzyme glyoxalase-I (Glo-I) is an essential therapeutic target in cancer treatment. Significant efforts have been made to discover competitive inhibitors of Glo-I as potential anticancer agents. Herein, we report the synthesis of a series of diazenylbenzenesulfonamide derivatives, their in vitro evaluation against Glo-I and the resulting structure-activity relationships. Among the compounds tested, compounds 9h and 9j exhibited the highest activity with IC50 1.28 µM and 1.13 µM, respectively. Docking studies to explore the binding mode of the compounds identified key moieties that may contribute to the observed activities. The active compounds will serve as suitable leads for further chemical optimization.

Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein.

AIMS: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein. METHODS: First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. Parallel, at all stages, the authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 with nCoV spike protein. RESULTS: Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein-protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. CONCLUSION: Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.

Identification of Human Leukotriene A4 Hydrolase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking.

Leukotriene B4 (LTB4) is a potent, proinflammatory lipid mediator implicated in the pathologies of an array of inflammatory diseases and cancer. The biosynthesis of LTB4 is regulated by the leukotriene A4 hydrolase (LTA4H). Compounds capable of limiting the formation of LTB4, through selective inhibition of LTA4H, are expected to provide potent anti-inflammatory and anti-cancer agents. The aim of the current study is to obtain potential LTA4H inhibitors using computer-aided drug design. A hybrid 3D structure-based pharmacophore model was generated based on the crystal structure of LTA4H in complex with bestatin. The generated pharmacophore was used in a virtual screen of the Maybridge database. The retrieved hits were extensively filtered, then docked into the active site of the enzyme. Finally, they were consensually scored to yield five hits as potential LTA4H inhibitors. Consequently, the selected hits were purchased and their biological activity assessed in vitro against the epoxide hydrolase activity of LTA4H. The results were very promising, with the most active compound showing 73.6% inhibition of the basal epoxide hydrolase activity of LTA4H. The results from this exploratory study provide valuable information for the design and development of more potent and selective inhibitors.

The Ethics of Gene Editing from an Islamic Perspective: A Focus on the Recent Gene Editing of the Chinese Twins.

In light of the development of "CRISPR" technology, new promising advances in therapeutic and preventive approaches have become a reality. However, with it came many ethical challenges. The most recent worldwide condemnation of the first use of CRISPR to genetically modify a human embryo is the latest example of ethically questionable use of this new and emerging field. Monotheistic religions are very conservative about such changes to the human genome and can be considered an interference with God's creation. Moreover, these changes could cause perpetual changes to future generations. The Muslim scholars establish their decisions by addressing five foundations of Islamic law i.e. "maqasid al sharī`a"; the purposes of the law. These are din̄ (religion), nafs (life), nasl (progeny), `aql (intellect) and mal (wealth). To achieve this, the five principles should all be met before approval of an experiment like the Chinese embryo modifications; Qasd (intention) which is achieved in this case as it aims to protect the embryo from HIV. Yaqin̄ (certainty) and Darar (injury) were not satisfied as they require strong scientific certainty of the procedures, and evidence of safety. Darura (necessity) by which the alternatives being compared; in this case more established and proven safe alternatives to protect the HIV transmission from the father are available, so this principle is not met. The final principle is `Urf (custom), by which the social context of using any contemporary technology should be taken in consideration, and clearly this was not achieved. Collectively, germline changes are rejected from an Islamic perspective until the five principles are fulfilled. In the Chinese Twins gene editing case, there was clearly no justification or support for it according to the Muslim Jurisprudence laws. These laws and approaches can serve as an ethical checklist for such controversial research, especially in early stages of the research.

Discovery of a nanomolar inhibitor of the human glyoxalase-I enzyme using structure-based poly-pharmacophore modelling and molecular docking.

The glyoxalase-I (GLO-I) enzyme, which is the initial enzyme of the glyoxalase system that is responsible for the detoxification of cytotoxic α-ketoaldehydes, such as methylglyoxal, has been approved as a valid target in cancer therapy. Overexpression of GLO-I has been observed in several types of carcinomas, including breast, colorectal, prostate, and bladder cancer. In this work we aimed to identify potential GLO-I inhibitors via employing different structure-based drug design techniques including structure-based poly-pharmacophore modelling, virtual screening, and molecular docking. Poly-pharmacophore modelling was applied in this study in order to thoroughly explore the binding site of the target enzyme, thereby, revealing hits that could bind in a nonconventional way which can pave the way for designing more potent and selective ligands with novel chemotypes. The modelling phase has resulted in the selection of 31 compounds that were biologically evaluated against human GLO-I enzyme. Among the tested set, seven compounds showed excellent inhibitory activities with IC50 values ranging from 0.34 to 30.57 µM. The most active compound (ST018515) showed an IC50 of 0.34 ± 0.03 µM, which, compared to reported GLO-I inhibitors, can be considered a potent inhibitor, making it a good candidate for further optimization towards designing more potent GLO-I inhibitors.

Withania somnifera root powder protects againist post-traumatic stress disorder-induced memory impairment.

Post-traumatic stress disorder (PTSD) is precipitated by exposure to severe traumatic events such as wars, natural disasters, catastrophes, or other traumatic events. Withania somnifera (WS) Dunal (family: Solanaceae) known traditionally as "Ashwaghanda" is used widely in ayurvedic medicine, and known to have positive role in neurodegenerative diseases. In this study, WS effect on impairment of memory due to PTSD was studied in animal models. Single-prolonged stress rat model, which consisted of restrain for 2 h, forced swimming for 20 min, rest for 15 min, and diethyl ether exposure for 1-2 min, was used to induce PTSD animals. The WS root powder extract was administered orally at a dose of 500 mg/kg/day. The radial arm water maze (RAWM) was used to assess spatial learning and memory. Enzymatic assays were used to evaluate changes in oxidative stress biomarkers in the hippocampus following treatments. The result showed that PTSD resulted in short- and long- term memory impairments. Administration of WS prevented this impairment of memory induced by PTSD. Furthermore, WS prevented PTSD induced changes in oxidative stress biomarker in the hippocampus. For quality assessment, the methanolic extract for WS was subjected to UHPLC analysis. A calibration curve for isowithanone as a marker compound was constructed. WS roots content of isowithanone was found to be 0.23% (w/w). In conclusion, WS administration prevented PTSD induced memory impairment probably through preserving changes in antioxidant mechanisms in the hippocampus.

Multi-Armed 1,2,3-Selenadiazole and 1,2,3-Thiadiazole Benzene Derivatives as Novel Glyoxalase-I Inhibitors.

Glyoxalase-I (Glo-I) enzyme was established to be a valid target for anticancer drug design. It performs the essential detoxification step of harmful byproducts, especially methylglyoxal. A robust computer-aided drug design approach was used to design and validate a series of compounds with selenium or sulfur based heterorings. A series of in-house multi-armed 1,2,3-selenadiazole and 1,2,3-thiadiazole benzene derivatives were tested for their Glo-I inhibitory activity. Results showed that these compounds bind Glo-I active sites competitively with strong potential to inhibit this enzyme with IC50 values in micro-molar concentration. Docking poses revealed that these compounds interact with the zinc atom at the bottom of the active site, which plays an essential role in its viability.

Computational and experimental exploration of the structure-activity relationships of flavonoids as potent glyoxalase-I inhibitors.

Hit, Lead & Candidate Discovery Glyoxalase-I (Glo-I) enzyme has emerged as a potential target for cancer treatment. Several classes of natural products including coumarins and flavonoids have shown remarkable Glo-I inhibitory activity. In the present study, computational and experimental approaches were used to explore the structure-activity relationships of a panel of 24 flavonoids as inhibitors of the Glo-1 enzyme. Scutellarein with an IC50 value of 2.04 µM was identified as the most potent inhibitor among the series studied. Di- or tri-hydroxylation of the benzene rings A and B accompanied with a C2/C3 double bond in ring C were identified as essential structural features for enzyme inhibition. Moreover, the ketol system showed a minor role in the inhibitory power of these compounds. The structure-activity relationships revealed in this study had deepened our understanding of the Glo-I inhibitory activities of flavonoids and opened the door for further exploration of this promising compound class.

A3, a Scorpion Venom Derived Peptide Analogue with Potent Antimicrobial and Potential Antibiofilm Activity against Clinical Isolates of Multi-Drug Resistant Gram Positive Bacteria.

Current research in the field of antimicrobials is focused on developing novel antimicrobial agents to counteract the huge dilemma that the human population is mainly facing in regards to the rise of bacterial resistance and biofilm infections. Host defense peptides (HDPs) are a promising group of molecules for antimicrobial development as they display several attractive features suitable for antimicrobial activity, including their broad spectrum of activity and potency against bacteria. AamAP1 is a novel HDP that belongs to the venom of the North African scorpion Androctonus amoeruxi. In vitro antimicrobial assays revealed that the peptide displays moderate activity against Gram-positive and Gram-negative bacteria. Additionally, the peptide proved to be highly hemolytic and displayed significantly high toxicity against mammalian cells. In our study, a novel synthetic peptide analogue named A3 was synthetically modified from AamAP1 in order to enhance its activity and toxicity profile. The design strategy depended on modifying the amino acid sequence of AamAP1 in order to alter its net positive charge, percentage helicity and modify other parameters that are involved theoretically in HDPs activity. Accordingly, A3 was evaluated for its in vitro antimicrobial and anti-biofilm activity individually and in combination with four different types of conventional antibiotics against clinical isolates of multi-drug resistant (MDR) Gram-positive bacteria. A3 was also evaluated for its cytotoxicity against mammalian cells. A3 managed to selectively inhibit the growth of a wide range of resistant strains of Gram-positive bacteria. Our results also showed that combining A3 with conventional antibiotics caused a synergistic antimicrobial behavior that resulted in decreasing the MIC value for A3 peptide as low as 0.125 µM. At the concentrations needed to inhibit bacterial growth, A3 displayed minimal mammalian cell toxicity. In conclusion, A3 exhibits enhanced activity and selectivity when compared with the parent natural scorpion venom peptide. The combination of A3 with conventional antibiotics could provide researchers in the antimicrobial drug development field with a potential alternative for conventional antibiotics against MDR bacteria.

Cytotoxic Homoisoflavones from the Bulbs of Bellevalia eigii.

Eight new and 10 known compounds were isolated from an organic extract of the bulbs of Bellevalia eigii as part of a search for anticancer leads from native plants of Jordan. Of these, the series of 16 homoisoflavonoids (1-16) comprise the seven new analogues 7-O-methyl-3'-hydroxy-3,9-dihydropunctatin (3), 6-hydroxy-7-O-methyl-3,9-dihydropunctatin (6), 7,4'-di-O-methyl-3'-hydroxy-3,9-dihydropunctatin (9), 7-O-methylpunctatin (10), 7-O-methyl-3'-hydroxypunctatin (13), 5-hydroxy-7,8-dimethoxychroman-4-one (14), and 7-O-methyl-8-demethoxy-3-hydroxy-3,9-dihydropunctatin (15). The known ferulic acid-derived acrylamide (17) and the new methylthioacrylate bellegimycin (18) are also reported. The structures were elucidated using a set of spectroscopic and spectrometric techniques; the absolute configurations of compounds 1-9, 15, and 16 were determined using ECD spectroscopy, while a modified Mosher's ester method was used for compound 18. Optical rotation data for the known compounds 1, 2, and 8 are reported here for the first time. The cytotoxic activities of all compounds were evaluated using the MDA-MB-435 (melanoma) and HT-29 (colon) cancer cell lines. Compounds 4 and 9 were the most potent on the latter cell line, with IC50 values of 1.0 and 1.1 µM, respectively. Compounds 1-18 were assessed for antimicrobial activity using a collection of bacteria and fungi; compounds 4 and 12 showed promising activity against the bacterium Mycobacterium smegmatis with MIC values of 17 and 24 µg/mL, respectively.

Chromatographic evaluation and QSAR optimization for benzoic acid analogues against carbonic anhydrase III.

An HPLC-size exclusion method was developed as an assay method to evaluate the binding of tested compounds with carbonic anhydrase III (CAIII) enzyme. Inhibition of CAIII by a group of benzoic acid analogues was characterized by vacancy (negative) peak intensity representing the fraction of the compounds bound with CAIII enzyme. Interestingly, p-hydroxyl benzoic acid and aspirin were found potent inhibitors against CAIII with affinity constants of 9954 and 9013 M(-1) respectively. Affinity values of twenty training compounds were modeled against thirty-five descriptors derived from their structures. Strong correlation was obtained between the affinity values and the formal charge of the molecules. Docking studies on training set compounds generated consensus scores having a strong agreement with affinity factors obtained from the chromatographic analysis.

Unraveling Potential Glyoxalase-I Inhibitors Utilizing Structure-Based Drug Design Techniques.

Background: Glyoxalase system detoxifies methylglyoxal and other ketoaldehydes to produce innocuous metabolites that allow the cells to function normally. Its inhibition in cancer cells causes these toxic metabolites to accumulate, and the cancer cells enter the apoptotic stage. Methods: The techniques of Computer-Aided Drug Design (CADD) were used, and the compounds possessing a zinc-binding group from commercial databases were extracted, using the pharmacophore search protocol. These compounds were subjected to robust docking using the CDOCKER protocol within the Discovery Studio. Docking was performed on both Glo-I twin active sites. The biological activities of candidate hits were assessed using an in vitro assay against Glo-I. Results: Compounds containing zinc-binding groups were extracted from ASINEX® commercial database, which contains (91,001 compounds). This step has helped to retrieve 1809 ligands, which then were prepared and docked at the two active sites of Glo-I. The fourteen compounds, which have showed the highest scores in docking and returned acceptable Total Binding Energy values, were purchased and tested against the enzyme in vitro. Two compounds out of the fourteen, which were selected in the final step, possess tetrazole ring as zinc chelating moiety, and have showed moderate activity with an IC50 of 48.18µM for SYN 25285236 and 48.77 µM for SYN 22881895. Conclusion: Two hits with moderate activity are identified as the lead compounds against Glo-I. Both compounds possess a negatively ionized tetrazole ring as the zinc-binding moiety. These compounds will lead to the development of inhibitors with improved activities.

Novel anthraquinone amide derivatives as potential glyoxalase-I inhibitors.

This study aimed to identify novel Glyoxalase-I (Glo-I) inhibitors with potential anticancer properties, focusing on anthraquinone amide-based derivatives. We synthesized a series of these derivatives and conducted in silico docking studies to predict their binding interactions with Glo-I. In vitro assessments were performed to evaluate the anti-Glo-I activity of the synthesized compounds. A comprehensive structure-activity relationship (SAR) analysis identified key features responsible for specific binding affinities of anthraquinone amide-based derivatives to Glo-I. Additionally, a 100 ns molecular dynamics simulation assessed the stability of the most potent compound compared to a co-crystallized ligand. Compound MQ3 demonstrated a remarkable inhibitory effect against Glo-I, with an IC50 concentration of 1.45 µM. The inhibitory potency of MQ3 may be attributed to the catechol ring, amide functional group, and anthraquinone moiety, collectively contributing to a strong binding affinity with Glo-I. Anthraquinone amide-based derivatives exhibit substantial potential as Glo-I inhibitors with prospective anticancer activity. The exceptional inhibitory efficacy of compound MQ3 indicates its potential as an effective anticancer agent. These findings underscore the significance of anthraquinone amide-based derivatives as a novel class of compounds for cancer therapy, supporting further research and advancements in targeting the Glo-I enzyme to combat cancer.

The practice of defensive medicine among Jordanian physicians: A cross sectional study.

BACKGROUND: Defensive medicine (DM) is a deviation from medical practice that is induced primarily by a threat of liability. While the DM behavior is well studied in the developed countries, little is known in developing countries and never been evaluated in Jordan. OBJECTIVE: To evaluate the prevalence of DM practice in Jordan among physicians and to investigate reasons behind its practice and potential strategies to alleviate this practice. METHODS: In this Cross-sectional study, self-administered questionnaire was distributed to a sample of physicians in both public and private sectors in Jordan. The collection period was from Jan 2021 to June 2021. The prevalence of DM practice was estimated among the study sample. Frequency scores of different DM behaviors, reasons of DM behaviors, and effectiveness of strategies in changing DM behaviors were summarized as average frequency scores with standard deviations. Multivariable linear regression models were conducted to evaluate potential predictors of total assurance and avoidance behavior scores. RESULTS: A total of 175 Jordanian physicians completed the survey. The prevalence of adopting (or witnessing) DM behaviors among the study sample was 68% (n = 119). Diagnostic laboratory exams followed by prescribed medications were the most practiced behaviors in excessive rate during a typical working week. Unfavorable legislation for the physician was reported as the headmost reason for practicing DM, followed by pressure from the public and mass media opinion. Continuous update of knowledge, abilities, and performance and following specific protocols and/or appropriate clinical evidence and appropriate multidisciplinary and multi-professional communication were the most effective strategies that can mitigate DM behaviors. CONCLUSIONS: Defensive medicine practice is common among Jordanian physicians with concerns about increasing pattern in the future.