The novel coronavirus SARS-CoV2, the causative agent of the pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide necessitated the discovery of new substances for anti-COVID-19 drug development. With the aid of bioinformatics and computational modelling, ninety seven antiviral secondary metabolites from fungi were docked onto five SARS-CoV2 enzymes involved in viral attachment, replication, post-translational modification, and host immunity evasion infection mechanisms followed by molecular dynamics simulation and in silico ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, three fumiquinazoline alkaloids scedapin C (15), quinadoline B (19) and norquinadoline A (20), the polyketide isochaetochromin D1 (8), and the terpenoid 11a-dehydroxyisoterreulactone A (11) exhibited high binding affinities on the target proteins, papain-like protease (PLpro), chymotrypsin-like protease (3CLpro), RNA-directed RNA polymerase (RdRp), non-structural protein 15 (nsp15), and the spike binding domain to GRP78. Molecular dynamics simulation was performed to optimize the interaction and investigate the stability of the top-scoring ligands in complex with the five target proteins. All tested complexes were found to have dynamic stability. Of the five top-scoring metabolites, quinadoline B (19) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.
The phenolic natural product magnolol exhibits neuroprotective properties through β-amyloid toxicity in PC-12 cells and ameliorative effects against cognitive deficits in a TgCRND8 transgenic mice model. Its bioavailability and blood–brain barrier crossing ability have been significantly improved using the metal–organic framework (MOF) UiO-66(Zr) as a drug delivery system (DDS). To investigate the neuroprotective effects of the Zr-based DDS, magnolol and magnolol-loaded-UiO-66(Zr) (Mag@UiO-66(Zr)) were evaluated for inhibitory activity against β-secretase and AlCl3-induced neurotoxicity. Due to the moderate inhibition observed for magnolol in vitro, in silico binding studies were explored against β-secretase along with 11 enzymes known to affect Alzheimer’s disease (AD). Favorable binding energies against CDK2, CKD5, MARK, and phosphodiesterase 3B (PDE3B) and dynamically stable complexes were noted through molecular docking and molecular dynamic simulation experiments, respectively. The magnolol-loaded DDS UiO-66(Zr) also showed enhanced neuroprotective activity against two pathological indices, namely, neutrophil infiltration and apoptotic neurons, in addition to damage reversal compared to magnolol. Thus, MOFs are promising drug delivery platforms for poorly bioavailable drugs.
A T-maze test is an experimental approach that is used in congenital research. However, the food reward-based protocol for the T-maze test in fish has low efficiency and a long training period. The aim of this study is to facilitate the T-maze conditions by using a combination of the principles of passive avoidance and a spatial memory test. In our modified T-maze settings, electric shock punishment (1–2 V, 0.3–0.5 mA) is given at the left arm, with a green cue at the right arm. Also, the depth of both arms of the T-maze was increased. The parameters measured in our T-maze design were latency, freezing time, and time spent in different areas of the T-maze. We validated the utility of our modified T-maze protocol by showing the consistent finding of memory impairment in ZnCl2−treated fish, which has been previously detected with the passive avoidance test. In addition, we also tested the spatial memory performance of leptin a (lepa) mutants which displayed an obesity phenotype. The results showed that although the learning and memory performance for lepa KO fish were similar to control fish, they displayed a higher freezing behavior during the training phase. In conclusion, we have established a modified T-maze protocol that can be used to evaluate the anxiety, learning, and memory capacity of adult zebrafish within three days, for the first time.
The novel coronavirus SARS-CoV2, the causative agent of the worldwide pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide have necessitated the need to discover substances that can be tapped for drug development. With the aid of bioinformatics and computational modelling, ninety seven secondary metabolites from fungi previously reported to exhibit antiviral properties were docked onto SARS-CoV2 enzymes involved in viral attachment, replication and post-translational mechanisms followed by <i>in silico</i> ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, two fumiquinazoline alkaloids quinadoline B (<b>19</b>), scedapin C (<b>15</b>), and the polyketide isochaetochromin D1 (<b>8</b>) exhibited high binding affinities depending on the target protein. The compounds were active against the cysteine proteases, papain-like protease (PLpro) and chymotrypsin-like protease (3CLpro) which are involved in post-translational modifications, RNA-directed RNA polymerase (RdRp) which is essential in viral replication, non-structural protein 15 (nsp15) which is involved in evasion of host immunity, and the spike protein which is responsible for binding to GRP78. Quinadoline B (<b>19</b>) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.
The novel coronavirus SARS-CoV2, the causative agent of the worldwide pandemic disease COVID-19, emerged in December 2019 forcing lockdown of communities in many countries. The absence of specific drugs and vaccines, the rapid transmission of the virus, and the increasing number of deaths worldwide have necessitated the need to discover substances that can be tapped for drug development. With the aid of bioinformatics and computational modelling, ninety seven secondary metabolites from fungi previously reported to exhibit antiviral properties were docked onto SARS-CoV2 enzymes involved in viral attachment, replication and post-translational mechanisms followed by <i>in silico</i> ADMET prediction (absorption, distribution, metabolism, excretion and toxicity) of the hit compounds. Thus, two fumiquinazoline alkaloids quinadoline B (<b>19</b>), scedapin C (<b>15</b>), and the polyketide isochaetochromin D1 (<b>8</b>) exhibited high binding affinities depending on the target protein. The compounds were active against the cysteine proteases, papain-like protease (PLpro) and chymotrypsin-like protease (3CLpro) which are involved in post-translational modifications, RNA-directed RNA polymerase (RdRp) which is essential in viral replication, non-structural protein 15 (nsp15) which is involved in evasion of host immunity, and the spike protein which is responsible for binding to GRP78. Quinadoline B (<b>19</b>) was predicted to confer favorable ADMET values, high gastrointestinal absorptive probability and poor blood-brain barrier crossing capacities.
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