Molecular docking and dynamics simulation analysis of the human FXIIa with compounds from the Mcule database.

The human factor XIIa is a serine protease enzyme that is implicated in the pathological thrombosis. This coagulation factor represents an interesting molecular target to design safer antithrombotic agents without adversely influencing physiological hemostasis. Therefore, it is of interest to virtually screen the human factor XIIa crystal with millions of compounds in Mcule database in order to identify potential inhibitors. For this purpose, both molecular docking and dynamics simulation were employed to identify potential hits. Also, various predictive approaches were utilized to estimate chemical, pharmacokinetics and toxicological features for the top hits. As such, we report here that compound 4 (1-(4-benzylpiperazin-1-yl)-2-[5-(3,5-dimethylpyrazol-1-yl)-1,2,3, 4-tetrazol-2-yl]ethanone) may be a potential ligand against the human factor XIIa for further consideration in the design and development of novel antithrombotic agents.

Design and construction of multi epitope- peptide vaccine candidate for rabies virus.

Rabies virus is a zoonotic pathogen that causes lethal encephalitis with a case fatality rate of almost 100% in unvaccinated individuals. The currently available vaccines against rabies are composed of inactivated viral particles that only confer a short-term immune response. It is well-known that the entry of rabies virus into host cells is mediated by a trimeric glycoprotein presents on the surface of viral envelope. As the sole viral surface protein, this trimeric glycoprotein represents a promising molecular target to design new vaccines and neutralizing antibodies against rabies virus. Epitope mapping studies had identified several antigenic sites on the surface of trimeric pre-fusion glycoprotein of rabies virus. Therefore, it is of interest to screen the rabies virus glycoprotein by different web-based immuno-informatics tools to identify potential B-cells and T-cells linear epitopes. Here, we present a construct of peptide vaccine that consists of these predicted linear epitopes of rabies virus glycoprotein together with appropriate linkers and adjuvant. Various online prediction tools, molecular docking and dynamics simulation assume that the vaccine construct may be stable, safe and effective. However, validation of these in-silico results is necessary both in vitro and in vivo setting.

The bioengineered and multifunctional nanoparticles in pancreatic cancer therapy: Bioresponisive nanostructures, phototherapy and targeted drug delivery.

The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor elimination. Because of the biological and malignant features of cancer cells, they have ability of developing resistance to conventional therapies such as chemo- and radio-therapy. Pancreatic cancer (PC) is a malignant disease of gastrointestinal tract in which chemotherapy and radiotherapy are main tools in its treatment, and recently, nanocarriers have been emerged as promising structures in its therapy. The bioresponsive nanocarriers are able to respond to pH and redox, among others, in targeted delivery of cargo for specific treatment of PC. The loading drugs on the nanoparticles that can be synthetic or natural compounds, can help in more reduction in progression of PC through enhancing their intracellular accumulation in cancer cells. The encapsulation of genes in the nanoparticles can protect against degradation and promotes intracellular accumulation in tumor suppression. A new kind of therapy for cancer is phototherapy in which nanoparticles can stimulate both photothermal therapy and photodynamic therapy through hyperthermia and ROS overgeneration to trigger cell death in PC. Therefore, synergistic therapy of phototherapy with chemotherapy is performed in accelerating tumor suppression. One of the important functions of nanotechnology is selective targeting of PC cells in reducing side effects on normal cells. The nanostructures are capable of being surface functionalized with aptamers, proteins and antibodies to specifically target PC cells in suppressing their progression. Therefore, a specific therapy for PC is provided and future implications for diagnosis of PC is suggested.

Molecular docking and dynamics simulation analysis of nucleoprotein from the Crimea-Congo hemorrhagic fever virus strain Baghdad-12 with FDA approved drugs.

Crimea-Congo hemorrhagic fever virus is considered a potential public health threat due to the high case fatality ratio of the disease hemorrhagic phase and absence of approved vaccines or antiviral agents. Therefore, it is of interest to screen FDA approved drugs against the nucleoprotein crystal of Crimea-Congo hemorrhagic fever virus strain Baghdad-12 by using molecular docking and dynamics simulation. Hence, we report that the beta receptor blocker Nebivolol and the antihistamine Loratadine may bind to RNA binding region on nucleoprotein for further consideration in drug design and development.

Towards the design of epitope candidates for Coronavirus 2.

The severe acute respiratory syndrome coronavirus-2, formerly known as 2019 novel coronavirus, is a pandemic public health threat. This beta coronavirus potentially infects the alveolar cells of the lung leading to pneumonia. The disease may progress into acute respiratory distress syndrome especially in elderly patients with comorbidities. Therefore, it is of interest to design and develop candidates for treatment, therapy and prevention. The spike glycoprotein of the virus known to potentially interact with angiotensin converting enzyme 2 as a cell entry receptor is a suitable candidate for further consideration as vaccine and treatment candidate. Hence, we screened the spike protein of coronavirus-2 for potential B-cell and T-cell epitopes for further deliberation. Thus, we document several peptides on the spike protein with predicted high antigenicity, low allergenicity and good stability against selected proteases. The linear B-cell epitope with sequence 'GFNCYFPLQSYGF' is of particular interest in this context towards the design and development of short peptide vaccine candidates for combat and care against the virus.

The Nrf2 Activator (DMF) and Covid-19: Is there a Possible Role?

INTRODUCTION: COVID-19 is a new viral illness that can affect the lungs and airways with lethal consequences leading to the death of the patients. The ACE2 receptors were widely disturbed among body tissues such as lung, kidney, small intestine, heart, and others in different percent and considered a target for the nCOVID-19 virus. S-protein of the virus was binding to ACE2 receptors caused downregulation of endogenous anti-viral mediators, upregulation of NF-κB pathway, ROS and pro-apoptotic protein. Nrf2 was a transcription factor that's play a role in generation of anti-oxidant enzymes. AIM: To describe and establish role of Nrf2 activators for treatment COVID-19 positive patients. METHODS: We used method of analysis of the published papers with described studies about COVID-19 connected with pharmacological issues and aspects which are included in global fighting against COVID-19 infection, and how using DMF (Nrf2 activator) in clinical trial for nCOVID-19 produce positive effects in patients for reduce lung alveolar cells damage. RESULTS: we are found that Nrf2 activators an important medication that's have a role in reduce viral pathogenesis via inhibit virus entry through induce SPLI gene expression as well as inhibit TRMPSS2, upregulation of ACE2 that's make a competition with the virus on binding site, induce gene expression of anti-viral mediators such as RIG-1 and INFs, induce anti-oxidant enzymes, also they have a role in inhibit NF-κB pathway, inhibit both apoptosis proteins and gene expression of TLRs. CONCLUSION: We are concluded that use DMF (Nrf2 activator) in clinical trial for nCOVID-19 positive patients to reduce lung alveolar cells damage.

Molecular docking and dynamics simulation of FDA approved drugs with the main protease from 2019 novel coronavirus.

Design and development of an effective drug to combat the 2019 novel coronavirus remains a challenge. Therefore, it is of interest to study the binding features of 1615 FDA approved drugs with the recently known 2019-nCoV main protease structure having high sequence homology with that from SARS-CoV. We document the binding features of top 10 drugs with the target protein. We further report that Conivaptan and Azelastine are mainly involved in hydrophobic interactions with active site residues. Both drugs can maintain close proximity to the binding pocket of main protease during simulation. However, these data need further in vitro and in vivo evaluation to repurpose these two drugs against 2019-nCoV.

The Pharmacist's Missing Role in the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In Wuhan, China, the disease was first identified in December 2019 and has since spread globally, resulting in the ongoing 2019-20 coronavirus pandemic. Several countries across the world are facing a shortage in frontline providers, while pharmacists are asked to cut working hours during this pandemic fight. Pharmacists as healthcare professionals could contribute in many aspects as responders to this pandemic worldwide if they had expanded education, training, and scope of practice.

Age Distribution of Clinical Symptoms, Isolation, Co-morbidities and Case Fatality Rate of COVID-19 Cases in Najaf City, Iraq.

INTRODUCTION: The first case of coronavirus disease 2019 (COVID-19) in holy Najaf city in February 22, 2020. The outbreak then rose up all over Iraq from 519 cases and 20 deaths in June 2, 2020 to 3484 cases and 72 deaths per day in August 10, 2020 per 24 hours. AIM: The aim of the study is to describe the distribution of confirmed cases by age, demographic factors, isolation, comorbidities and case fatality rate. METHODS: Prospectively collected and analyzed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. The demographic and clinical outcomes data of 1153 diagnosed patients were collected from consecutive patients, analyzed, and described. About two third of cases 789 (68.4%) acquired infection through contact with positive patients. RESULTS: The reported cases were 743 (64.4%) males and 410 (35.6%) females with large number among age range 21 to 50 years. The most frequent presenting symptoms were fever, sore throat and dyspnea or cough, most of patients; 868 (75%) patients were isolated at home versus 285 (24.72) patients required hospitalization which represented the intermediate and sever cases. The overall case fatality rate was 2.4%. CONCLUSION: Most of COVID-19 cases in this locality were male from urban areas. The common onset symptoms were the fever, sore throat and dyspnea or cough. Majority of cases were isolated and treated at home. The estimated case fatality rate was within the global range (2.4%).

Molecular docking enabled updated screening of the matrix protein VP40 from Ebola virus with millions of compounds in the MCULE database for potential inhibitors.

Ebola virus is known for several outbreaks of hemorrhagic fever in West Africa. This RNA virus is linked to high fatality and easy transmission. Recently, an effective vaccine and a monoclonal antibody cocktail have been introduced to combat Ebola virus infection. The matrix protein VP40 of Ebola virus is a known drug target and it is essential for viral life cycle through participation in RNA transcription as well as for the budding of the mature virus. It is known that residues phenylalanine 125 and arginine 134 of VP40 are involved in the interaction with RNA. Therefore, it is of interest to screen VP40 with millions of compounds at the mcule.com database for potential inhibitors. The output hits were ranked according to their minimum binding energy to matrix protein VP40. We further calculated the pharmacokinetics and toxicology properties for the best five hits using several predictive ADME analysis web tools. We report a candidate lead (compound #5: ((10R)-10-(4-hydroxyphenyl)-11,12,14,16-tetraazatetracyclo[7.7.0.02,7.011,15] hexadeca-1(16), 2(7),3,5,8,12,14-heptaen-8-ol)) with high drug-likeness score, promising lead-likeness behaviour and high median lethal dose. The candidate lead compound #5 engages in hydrogen bonding and hydrophobic interactions with VP40 active site residues. Thus, the lead compound #5 is recommended for further in vitro and in vivo validations for further consideration.