A Computational Study on Selected Alkaloids as SARS-CoV-2 Inhibitors: PASS Prediction, Molecular Docking, ADMET Analysis, DFT, and Molecular Dynamics Simulations.

Despite treatments and vaccinations, it remains difficult to develop naturally occurring COVID-19 inhibitors. Here, our main objective is to find potential lead compounds from the retrieved alkaloids with antiviral and other biological properties that selectively target the main SARS-CoV-2 protease (Mpro), which is required for viral replication. In this work, 252 alkaloids were aligned using Lipinski's rule of five and their antiviral activity was then assessed. The prediction of activity spectrum of substances (PASS) data was used to confirm the antiviral activities of 112 alkaloids. Finally, 50 alkaloids were docked with Mpro. Furthermore, assessments of molecular electrostatic potential surface (MEPS), density functional theory (DFT), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) were performed, and a few of them appeared to have potential as candidates for oral administration. Molecular dynamics simulations (MDS) with a time step of up to 100 ns were used to confirm that the three docked complexes were more stable. It was found that the most prevalent and active binding sites that limit Mpro'sactivity are PHE294, ARG298, and GLN110. All retrieved data were compared to conventional antivirals, fumarostelline, strychnidin-10-one (L-1), 2,3-dimethoxy-brucin (L-7), and alkaloid ND-305B (L-16) and were proposed as enhanced SARS-CoV-2 inhibitors. Finally, with additional clinical or necessary study, it may be able to use these indicated natural alkaloids or their analogs as potential therapeutic candidates.

Potential candidates from marine and terrestrial resources targeting mitochondrial inhibition: Insights from the molecular approach.

Mitochondria are the target sites for multiple disease manifestations, for which it is appealing to researchers' attention for advanced pharmacological interventions. Mitochondrial inhibitors from natural sources are of therapeutic interest due to their promising benefits on physiological complications. Mitochondrial complexes I, II, III, IV, and V are the most common sites for the induction of inhibition by drug candidates, henceforth alleviating the manifestations, prevalence, as well as severity of diseases. Though there are few therapeutic options currently available on the market. However, it is crucial to develop new candidates from natural resources, as mitochondria-targeting abnormalities are rising to a greater extent. Marine and terrestrial sources possess plenty of bioactive compounds that are appeared to be effective in this regard. Ample research investigations have been performed to appraise the potentiality of these compounds in terms of mitochondrial disorders. So, this review outlines the role of terrestrial and marine-derived compounds in mitochondrial inhibition as well as their clinical status too. Additionally, mitochondrial regulation and, therefore, the significance of mitochondrial inhibition by terrestrial and marine-derived compounds in drug discovery are also discussed.

Prognostic significance of programmed death-1 and programmed death ligand-1 proteins in breast cancer.

In numerous studies related to tumor prognosis, programmed death-ligand 1 (PD-L1) has been identified as a biomarker. This work aimed to determine the prognostic importance of PD-L1 in breast cancer. We searched electronic databases such as PubMed, Google scholar, home pages of publishing groups, medical, clinical, and pharmaceutical sciences journals, as well as other relevant sources to discover the importance of PD-1 and PD-L1 expression in breast cancer therapies and also recurrence. The keywords used in this search were autoimmunity, programmed cell death, PD-L1 or PD-1, and breast cancer. Our inclusion criteria included studies showing the synergy between the expression of PD-L1 and PD-1 in primary breast cancers as prognostic markers and this research was limited to humans only. We included review articles, original research, letters to the editor, case reports, and short communications in our study, published in English. We focused our work on PD-L1 mRNA expression in breast cancer cell lines. PD-L1 expression has been decisively demonstrated to be a high-risk factor for breast cancer with a bad prognosis.