QSAR and DFT Studies of Some Tacrine-Hydroxamate Derivatives as Inhibitors of Cholinesterase (AChEs) in the Treatment of Alzheimer's Disease

Introduction: This work was devoted to an in silico investigation conducted on twenty-eight Tacrine-hydroxamate derivatives as a potential treatment for Alzheimer's disease using DFT and QSAR modeling techniques. Method(s): The data set was randomly partitioned into a training set (22 compounds) and a test set (6 compounds). Then, fourteen models were built and were used to compute the predicted pIC50 of compounds belonging to the test set. Result(s): Al built models were individualy validated using both internal and external validation methods, including the Y-Randomization test and Golbraikh and Tropsha's model acceptance criteria. Then, one model was selected for its higher R2, R2test, and Q2cv values (R2 = 0.768, R2adj = 0.713, MSE = 0.304, R2test=0.973, Q2cv = 0.615). From these outcomes, the activity of the studied compounds toward the main protease of Cholinesterase (AChEs) seems to be influenced by 4 descriptors, i.e., the total dipole moment of the molecule (mu), number of rotatable bonds (RB), molecular topology radius (MTR) and molecular topology polar surface area (MTPSA). The effect of these descriptors on the activity was studied, in particular, the increase in the total dipole moment and the topological radius of the molecule and the reduction of the rotatable bond and topology polar surface area increase the activity. Conclusion(s): Some newly designed compounds with higher AChEs inhibitory activity have been designed based on the best-proposed QSAR model. In addition, ADMET pharmacokinetic properties were carried out for the proposed compounds, the toxicity results indicate that 7 molecules are nontoxic.Copyright © 2023 Bentham Science Publishers.

INSIGHT OF PANDEMIC COVID-19: DEVELOPMENTS AND CHALLENGES

This review focuses on the characteristics of coronavirus disease-19 (COVID-19) including virus structure, ecoepidemiology and pathophysiology, signs and symptoms in infected people, and data on virus pathogenicity, severity, and survivability in COVID-19 infected patients. The emphasis is on immunological reactions, diagnosis, prophylactic methods, and the zoonotic significance of COVID-19. The authors feel that the review's contents will be valuable to epidemiologists, virologists, public health officials, diagnosticians, laboratory workers, environmentalists, and socioeconomic experts. It has information on the many types of coronavirus variants, the disease situation in Pakistan and the WHO criteria for COVID-19 prevention is given. Moreover, lessons learned from the COVID-19 pandemic are also outlined.

Phages and SARS-CoV-2

The emerging human pathogenic viruses, including the recently emerged severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), have markedly affected the human health and have become a challenge for researchers worldwide. Antibiotic therapy and existing vaccines have reduced the pandemic burden to some extent. However, there is still need for efficient treatment, vaccination, and antiviral agents to control the pandemic. This chapter illustrates the role of bacteriophage in bacterial infections, SARS-COV-2 infected patients, biological activities of phages, phage display method, phages as potential inducers of antiviral immunity, phage-based vaccines, CRISPR and phage-based SARS-CoV-2 vaccines, and possible advantages of phage-based vaccines. It is concluded that phages have considerable breadth in the SARS-CoV-2 pandemic and offer many substantial advantages, such as clearing respiratory bacterial infections, which significantly reduce the burden of mortalities. Phage plays a vital role in triggering antiviral immunity by inducing cytokines such as IFN-α and IL-12. It suggests the role in driving antiviral immunity, triggering TLR3-dependent pattern recognition receptors, inhibiting TNF-driving type I IFN, inducing antiviral immunity through upregulation of the expression of defensin in IL-2, and encouraging a marked upregulation of gene hBD2 that induces virucidal effects, thus playing a key role in anti-SARS-COV-2 immunity. Moreover, phages have been presented as an alternative universal adjuvant-free nano-vaccine platform in which single-phage scaffolds are used to incorporate multiple targets. © 2023 Elsevier Inc. All rights reserved.

Natural products and SARS-CoV-2

Natural products have been proven to be the source of many antiviral drugs in the past. History has a bunch of natural products used as traditional medicine, therapies, mixtures, and oils. However, there are many bioactive natural products that need to be evaluated against severe acute respiratory syndrome (SARS-CoV-2) to curb the ongoing pandemic. Several plants and fungal-derived natural products are extensively reported with antiviral activities against SARS-CoV-2. In vitro, preliminary study assays and computational studies revealed several antiviral drugs from natural fungal compounds, including cordycepin isolated from Cordyceps militaris fungi. Polyphenolic compounds isolated from the Broussonetia papyrifera plant showed promising antiviral activity against SARS CoV-2 in in silico studies. Two alkaloid compounds, 10-hydroxyusambarensine and cryptoquindoline isolated from African medicinal plants, inhibited the main protease (Mpro) of SARS CoV-2. At the start of the COVID-19 pandemic, FDA approved the emergency use of chloroquine against SARS CoV-2;chloroquine is a derivative of alkaloid. The development of modern technologies has streamlined the discovery of new drugs from natural products. Gas chromatography–mass spectrometry, infrared radiation, nuclear magnetic resonance, high-performance thin-layer chromatography, and high-performance liquid chromatography and other high output technologies should be available for the structural interpretation and distinguishability of prudent lead molecules © 2023 Elsevier Inc. All rights reserved.

In Silico Approach for Designing Novel SARS-CoV-2 Inhibitors from Medicinal Plants

Several countries in the world, are still under the threat of SARS-CoV-2 propagation, although the majority of the population has received a vaccine. Some ethno-botanical surveys were conducted to document potential herbal remedies that can be used in the management of the COVID-19 pandemic in Cameroon. Medicinal plants belonging to Cameroon flora could be a source for the discovery of potential inhibitors of SARS-CoV-2Mpro and spike proteins. These two proteins play a pivotal role in mediating viral replication and transcription, making them attractive targets for drug design against SARS-CoV-2. The aim of this in silico study is to evaluate the behavior of the isolated secondary metabolites from Cameroonian medicinal plant species towards SARS-CoV-2Mpro and spike proteins. In the present study, six plant species are selected among the frequently used plants to treat COVID-19 and related symptoms in Cameroon. To highlight the interactions of studied secondary metabolites with SARS-CoV-2Mpro (6lu7) and spike (6m0j) proteins a molecular docking analysis is used. Among the one hundred and twenty-five screened compounds, thirty-five showed high binding affinity against the two targeted proteins. Furthermore, molecular dynamics simulations were performed to support the docking results. Additional investigations, including physicochemical properties, pharmacokinetics, and toxicological profile show that only twelve compounds bind tightly to Mpro (6lu7) and spike (6m0j) proteins and could be considered as promising drug candidates of SARS-CoV-2. The selected twelve compounds are evaluated for their acute and chronic toxicity, possible mutagenic, tumorigenic, irritant, and reproductive effectiveness. The outcomes of this study suggest the possibility of developing potent Mpro and spike proteins inhibitors from naturally occurring compounds belonging to Cameroon flora. © 2022,Physical Chemistry Research. All Rights Reserved.