Chemi-Informatic Approach to Investigate Putative Pharmacoactive Agents of Plant Origin to Eradicate COVID-19

Background: The scientific community has supported the medicinal flora of ancient as well as modern times in extracting chemicals, which holds therapeutic potential. In many previous studies, Amentoflavone discovered as an anti-viral agent, and it is present as a bioactive constituent in many plants of different families like Selaginellaceae, Euphorbiaceae, and Calophyllaceae. Withania somnifera (Ashwagandha) is already considered a significant anti-viral agent in traditional medicine, and it is the main source of Somniferine-A and Withanolide-B. Objective(s): In this study, phytochemicals such as withanolide-b, somniferine-a, stigmasterol, amentoflavone, and chavicine were analyzed to screen protein inhibitors, out of them;such proteins are involved in the internalization and interaction of SARS-CoV-2 with human cytological domains. This will help in developing a checkpoint for SARS-CoV-2 internalization. Method(s): Chemi-informatic tools like basic local alignment search tool (BLAST), AutoDock-vina, SwissADME, MDWeb, Molsoft, ProTox-II, and LigPlot were used to examine the action of pharmacoactive agents against SARS-CoV-2. The tools used in the study were based on the finest algorithms like artificial neural networking, machine learning, and artificial intelligence. Result(s): On the basis of binding energies less than equal to-8.5 kcal/mol, amentoflavone, stigmasterol, and somniferine-A were found to be the most effective against COVID-19 disease as these chemical agents exhibit hydrogen bond interactions and competitively inhibit major proteins (SARS-CoV-2 Spike, Human ACE-2 receptor, Human Furin protease, SARS-CoV-2 RNA binding protein) that are involved in its infection and pathogenesis. Simulation analysis provides more validity to the selection of the drug candidate Amentoflavone. ADMET properties were found to be in the feasible range for putative drug candidates. Conclusion(s): Computational analysis was successfully used for searching pharmacoactive phytochemicals like Amentoflavone, Somniferine-A, and Stigmasterol that can bring control over COVID-19 expansion. This new methodology was found to be efficient, as it reduces monetary expenditures and time consumption. Molecular wet-lab validations will provide approval for finalizing our selected drug model for controlling the COVID-19 pandemic.Copyright © 2022 Bentham Science Publishers.

ROLE OF IFNgamma IN PATHOGENESIS OF SARS-CoV-2 INFECTION.

To date, there is no consensus explaining the relationship between varying concentrations of IFNgamma and the severity of infection caused by SARS-CoV-2. The aim of this article was to analyze and formulate conclusions from the selected studies and publications, which, in sum, provide a potentially reasonable view on the role of IFNgamma in COVID-19 pathogenesis. This article highlights current data on the immunological role of IFNgamma which affects differentiation of naive T helper cells, acting as a polarizing factor. It activates the major histocompatibility complex (MHC) class I and II, by increasing the expression of MHC I/II subunits, inhibiting replication of the viral particles by initiating activation of interferon-stimulated genes followed by subsequent synthesis of antiviral proteins. Moreover, IFNgamma activates the production of cytokines by T cells, enhancing cytotoxic activity of the T killers. IFNgamma exerts immunostimulatory and immunomodulatory effects via STAT1, SOCS1 and PIAS genes, thus regulating activation of the JAK-STAT signaling pathway. A number of studies were considered where the patterns of changes in serum IFNgamma concentration were examined in viral infections and SARS-CoV-2. We performed a systemic analysis of the results of studies that showed a relationship between high concentrations of IFNgamma and COVID-19 severity. In a number of studies, the significantly high levels of IFNgamma in COVID-19 patients were often associated with a poor outcome of the disease. The median values of the IFNgamma concentration in severe COVID-19 were found to be significantly higher compared to the results obtained in the cases of moderate severity. It shows an increase, in parallel with viral load in the nasopharyngeal samples upon worsening of the clinical condition. Based on the data on the decreased IFNgamma concentrations in convalescent patients, the mechanism of antagonism between IFNgamma and IL-4 is considered, where the decreases serum concentrations of IFNgamma along with increasing level of IL-4 may be an indirect proof of normal adaptive immune response with subsequent development of antibodies to SARS-CoV-2 and gradual elimination of the virus from the body. Moreover, the evidence is discussed that the patients harboring some parasitic infections (Toxoplasma gondii, Cryptosporidium, Blastocystis hominis, Giardia duodenalis, Entamoeba histolytica) with persistently elevated level of IFNgamma are at reduced risk for severe course of COVID-19. Copyright © 2022, SPb RAACI.

GC-MS Analysis and Molecular Docking Studies to Identify Potential SARS-CoV-2 Nonstructural Protein Inhibitors from Icacina trichantha Oliv Tubers

The COVID-19 pandemic, caused by the SARS-CoV-2, has prompted international concern. This research aims to find bioactive phytocompounds from the traditional herb Icacina trichantha (Oliv) that could be used as a possible SARS-CoV-2 nonstructural protein inhibitor. GC-MS analysis identified fifteen (15) phytocompounds. In silico molecular docking, drug-likeness, toxicity and prediction of these compounds’ substance activity spectra (PASS) were evaluated. The phytocompounds all have good binding energies, according to molecular docking. The phytocompound, 9,12-octadecanoic acid gave the best binding affinity of-24.98 kcal/mole. All of the identified compounds conformed to Lipinski’s Rule of Five (RO5). This showed that the identified I. trichantha (Oliv) compounds would have lower attrition rates during clinical trials and thus have a better chance of being marketed. The current findings suggest that the discovered phytocompounds of I. trichantha (Oliv) could be developed as a novel COVID-19 medication.

21stRSC/SCI Medicinal Chemistry Symposium Cambridge/Virtual - September 13-15, 2021

The Royal Chemistry Society/Society of Chemistry Industry (RSC/SCI) Medicinal Chemistry Symposium is a key symposium in the field of medicinal chemistry that takes place every 2 years at the University of Cambridge, U.K., under the auspices of the RSC and the SCI. This year, in its 21st edition, it was run as a hybrid event, simultaneously attended by both in-person and virtual attendees. Its theme was 'Improving Success', and 25 orals and 30 posters were presented. The scientific program covered recent medicinal chemistry achievements in major therapeutic areas, with a few first-time structure disclosure presentations and particular emphasis on emerging early-stage drug discovery and lead optimization strategies, including reports of successful case studies illustrating fragment-based screening and phenotypic target engagement approaches. Applications of artificial intelligence (AI), mass spectrometry and photochemistry in drug design and discovery were also highlighted. This report will cover some of the medicinal chemistry presentations delivered at the meeting.

Diagnostic and therapeutic recommendations of the Polish Society of Haematologists and Transfusiologists and Polish Adult Leukemia Group-CLL for chronic lymphocytic leukemia in 2021

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age at diagnosis of approximately 70 years. The natural course of the disease varies greatly, and patients with non-progressive and asymptomatic leukemia do not require treatment. The results of CLL treatment have improved significantly in recent years, mainly due to the introduction of new, more effective drugs, including BCR inhibitors and BCL2 inhibitors. The new drugs are used continuously, while venetoclax in combination with anti-CD20 antibodies is used for 24 (rituximab) or 12 (obinutuzumab) months, depending on the type of antibody and line of therapy. The choice of treatment protocol should largely depend on the assessment of 17p deletion/TP53 mutation and immunoglobulin variable heavy chain (IGVH) mutation status, which correlate with a worse response to immunochemotherapy. The role of immunochemotherapy, which until recently was the mainstay of CLL treatment, has now significantly decreased. In the first-line, it is recommended only in patients without 17p deletion/TP53 mutation, with mutated IGVH. Other patients should receive novel targeted therapies. However, at the time of the preparation of these recommendations, these therapies are not available in the firs-line of treatment in Poland. Novel targeted therapies play a major role in the treatment of refractory/relapsed CLL, and immunochemotherapy is recommended primarily in patients with a long-term response to first-line therapy. In this article, we present an update of the guidelines for the diagnosis and treatment of CLL, including the treatment of autoimmune complications, as well as the prophylaxis and treatment of infections, developed by the Polish Society of Haematologists and Transfusiologists and PALG-CLL Working Group.

Generation of an anticoagulant aptamer that targets factor V/Va and disrupts the FVa-membrane interaction in normal and COVID-19 patient samples.

Coagulation cofactors profoundly regulate hemostasis and are appealing targets for anticoagulants. However, targeting such proteins has been challenging because they lack an active site. To address this, we isolate an RNA aptamer termed T18.3 that binds to both factor V (FV) and FVa with nanomolar affinity and demonstrates clinically relevant anticoagulant activity in both plasma and whole blood. The aptamer also shows synergy with low molecular weight heparin and delivers potent anticoagulation in plasma collected from patients with coronavirus disease 2019 (COVID-19). Moreover, the aptamer's anticoagulant activity can be rapidly and efficiently reversed using protamine sulfate, which potentially allows fine-tuning of aptamer's activity post-administration. We further show that the aptamer achieves its anticoagulant activity by abrogating FV/FVa interactions with phospholipid membranes. Our success in generating an anticoagulant aptamer targeting FV/Va demonstrates the feasibility of using cofactor-binding aptamers as therapeutic protein inhibitors and reveals an unconventional working mechanism of an aptamer by interrupting protein-membrane interactions.

The reality of ai in drug discovery. highlights from the society for medicines research online meeting

The Society for Medicines Research held a meeting reviewing recent practical progress in the application of artificial intelligence (AI) in drug discovery. This is an area receiving very significant interest in both large pharmaceutical and biotech sectors, and academia, for the potential to impact and increase efficiency of drug discovery, with many partnerships announced between large pharma companies and AI start-ups. This partnering interest and potential commercial value have led to intensive interest from investors. Recent highlights (as of March 2021) of investor commitment include a USD 100M fundraising by the U.K. AI company ExScientia Ltd., and a USD 400M raise by the U.S. company Insitro Inc. Key technology advances enabling this activity include i) deep learning software and toolkits, ii) the availability of graphics processing unit (GPU) compute power, and iii) access to large relevant datasets for training and validation, all leading to many notable publications. However, as with all new technologies, there is always the need to align them to the optimal part of a business process, and arguably the pharmaceutical industry is just at the start of realizing the potential and understanding the key application areas to apply AI. The meeting brought together established thought leaders and practitioners reviewing the current reality of AI approaches in drug discovery.