The Discovery of Novel Small Oxindole-Based Inhibitors Targeting the SARS-CoV-2 Main Protease (Mpro ).

With the potential for coronaviruses to re-emerge and trigger future pandemics, the urgent development of antiviral inhibitors against SARS-CoV-2 is essential. The Mpro enzyme is crucial for disease progression and the virus's life cycle. It possesses allosteric sites that can hinder its catalytic activity, with some of these sites located at or near the dimerization interface. Among them, sites #2 and #5 possess druggable pockets and are predicted to bind drug-like molecules. Consequently, a commercially available ligand library containing ~7 million ligands was used to target site #2 via structure-based virtual screening. After extensive filtering, docking, and post-docking analyses, 53 compounds were chosen for biological testing. An oxindole derivative was identified as a Mpro non-competitive reversible inhibitor with a Ki of 115 µM and an IC50 of 101.9 µM. Throughout the 200 ns-long MD trajectories, our top hit has shown a very stable binding mode, forming several interactions with residues in sites #2 and #5. Moreover, derivatives of our top hit were acquired for biological testing to gain deeper insights into their structure-activity relationship. To sum up, drug-like allosteric inhibitors seem promising and can provide us with an additional weapon in our war against the recent pandemic, and possibly other coronaviruses-caused diseases.

Apolipoprotein E Genetic Variant and Blood Lipid Responses to Plant Sterols: A Systematic Review and Pooled Analysis of Clinical Trials.

Plant sterols/stanols are effective cholesterol-lowering agents. However, it is unclear whether the apolipoprotein E (ApoE) genetic variants influence it. We investigated whether ApoE genetic variants modulate the responses of blood lipids to dietary intervention plant sterols/stanols in adults and if the intervention dose and duration, as well as the age and status of participants, influence this effect. Randomized clinical trials were identified by searching databases in the Cochrane Library. Random-effect models were used to estimate the pooled effect size of each outcome of interest total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and triglycerides. Meta-regression and subgroup analysis were used to investigate the effects of potential modifiers on the outcomes of interest. Eleven articles were selected from 3,248 retrieved abstracts. Plant sterol/stanol intervention was associated with a more significant reduction in LDL levels in the E3 group [-0.251 mmol/L; 95% confidence interval (95% CI), -0.488 to -0.015] compared with both the E4 and E2 groups. In E4 carriers, the plant sterol/stanol intervention dose and duration resulted in a larger decrease in LDL levels (-0.088027 mmol/L; 95% CI, -0.154690 to -0.021364). In conclusion, ApoE genetic variants affected the response of blood LDL levels to supplementation with plant sterols/stanols, as individuals with E3 variant showed significantly decreased LDL levels compared with the other genotypes. However, future studies recruiting participants according to their ApoE genetic variants are needed to confirm our conclusion.

The Discovery of Small Allosteric and Active Site Inhibitors of the SARS-CoV-2 Main Protease via Structure-Based Virtual Screening and Biological Evaluation.

The main protease enzyme (Mpro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the Mpro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with Ki values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.

Allosteric Binding Sites of the SARS-CoV-2 Main Protease: Potential Targets for Broad-Spectrum Anti-Coronavirus Agents.

The current pandemic caused by the COVID-19 disease has reached everywhere in the world and has affected every aspect of our lives. As of the current data, the World Health Organization (WHO) has reported more than 300 million confirmed COVID-19 cases worldwide and more than 5 million deaths. Mpro is an enzyme that plays a key role in the life cycle of the SARS-CoV-2 virus, and it is vital for the disease progression. The Mpro enzyme seems to have several allosteric sites that can hinder the enzyme catalytic activity. Furthermore, some of these allosteric sites are located at or nearby the dimerization interface which is essential for the overall Mpro activity. In this review paper, we investigate the potential of the Mpro allosteric site to act as a drug target, especially since they interestingly appear to be resistant to mutation. The work is illustrated through three subsequent sections: First, the two main categories of Mpro allosteric sites have been explained and discussed. Second, a total of six pockets have been studied and evaluated for their druggability and cavity characteristics. Third, the experimental and computational attempts for the discovery of new allosteric inhibitors have been illustrated and discussed. To sum up, this review paper gives a detailed insight into the feasibility of developing new Mpro inhibitors to act as a potential treatment for the COVID-19 disease.

Structure-Activity Relationship of Benzofuran Derivatives with Potential Anticancer Activity.

Benzofuran is a heterocyclic compound found naturally in plants and it can also be obtained through synthetic reactions. Multiple physicochemical characteristics and versatile features distinguish benzofuran, and its chemical structure is composed of fused benzene and furan rings. Benzofuran derivatives are essential compounds that hold vital biological activities to design novel therapies with enhanced efficacy compared to conventional treatments. Therefore, medicinal chemists used its core to synthesize new derivatives that can be applied to a variety of disorders. Benzofuran exhibited potential effectiveness in chronic diseases such as hypertension, neurodegenerative and oxidative conditions, and dyslipidemia. In acute infections, benzofuran revealed anti-infective properties against microorganisms like viruses, bacteria, and parasites. In recent years, the complex nature and the number of acquired or resistant cancer cases have been largely increasing. Benzofuran derivatives revealed potential anticancer activity with lower incidence or severity of adverse events normally encountered during chemotherapeutic treatments. This review discusses the structure-activity relationship (SAR) of several benzofuran derivatives in order to elucidate the possible substitution alternatives and structural requirements for a highly potent and selective anticancer activity.

Structure-based assessment and druggability classification of protein-protein interaction sites.

The featureless interface formed by protein-protein interactions (PPIs) is notorious for being considered a difficult and poorly druggable target. However, recent advances have shown PPIs to be druggable, with the discovery of potent inhibitors and stabilizers, some of which are currently being clinically tested and approved for medical use. In this study, we assess the druggability of 12 commonly targeted PPIs using the computational tool, SiteMap. After evaluating 320 crystal structures, we find that the PPI binding sites have a wide range of druggability scores. This can be attributed to the unique structural and physiochemical features that influence their ligand binding and concomitantly, their druggability predictions. We then use these features to propose a specific classification system suitable for assessing PPI targets based on their druggability scores and measured binding-affinity. Interestingly, this system was able to distinguish between different PPIs and correctly categorize them into four classes (i.e. very druggable, druggable, moderately druggable, and difficult). We also studied the effects of protein flexibility on the computed druggability scores and found that protein conformational changes accompanying ligand binding in ligand-bound structures result in higher protein druggability scores due to more favorable structural features. Finally, the drug-likeness of many published PPI inhibitors was studied where it was found that the vast majority of the 221 ligands considered here, including orally tested/marketed drugs, violate the currently acceptable limits of compound size and hydrophobicity parameters. This outcome, combined with the lack of correlation observed between druggability and drug-likeness, reinforces the need to redefine drug-likeness for PPI drugs. This work proposes a PPI-specific classification scheme that will assist researchers in assessing the druggability and identifying inhibitors of the PPI interface.