Impact of SNPs, off-targets, and passive permeability on efficacy of BCL6 degrading drugs assigned by virtual screening and 3D-QSAR approach.

B-cell lymphoma 6 (BCL6) regulates various genes and is reported to be overexpressed in lymphomas and other malignancies. Thus, BCL6 inhibition or its tagging for degradation would be an amenable therapeutic approach. A library of 2500 approved drugs was employed to find BCL6 inhibitory molecules via virtual screening. Moreover, the 3D core structure of 170 BCL6 inhibitors was used to build a 3D QSAR model and predict the biological activity. The SNP database was analyzed to study the impact on the destabilization of BCL6/drug interactions. Structural similarity search and molecular docking analyses were used to assess the interaction between possible off-targets and BCL6 inhibitors. The tendency of drugs for passive membrane permeability was also analyzed. Lifitegrast (DB11611) had favorable binding properties and biological activity compared to the BI-3802. Missense SNPs were located at the essential interaction sites of the BCL6. Structural similarity search resulted in five BTB-domain containing off-target proteins. BI-3802 and Lifitegrast had similar chemical behavior and binding properties against off-target candidates. More interestingly, the binding affinity of BI-3802 (against off-targets) was higher than Lifitegrast. Energetically, Lifitegrast was less favorable for passive membrane permeability. The interaction between BCL6 and BI-3802 is more prone to SNP-derived variations. On the other hand, higher nonspecific binding of BI-3802 to off-target proteins could bring about higher undesirable properties. It should also be noted that energetically less desirable passive membrane translocation of Lifitegrast would demand drug delivery vehicles. However, further empirical evaluation of Lifitegrast would unveil its true potential.

A unique antigen against SARS-CoV-2, Acinetobacter baumannii, and Pseudomonas aeruginosa.

The recent outbreak of COVID-19 has increased hospital admissions, which could elevate the risk of nosocomial infections, such as A. baumannii and P. aeruginosa infections. Although effective vaccines have been developed against SARS-CoV-2, no approved treatment option is still available against antimicrobial-resistant strains of A. baumannii and P. aeruginosa. In the current study, an all-in-one antigen was designed based on an innovative, state-of-the-art strategy. In this regard, experimentally validated linear epitopes of spike protein (SARS-CoV-2), OmpA (A. baumannii), and OprF (P. aeruginosa) were selected to be harbored by mature OmpA as a scaffold. The selected epitopes were used to replace the loops and turns of the barrel domain in OmpA; OprF311-341 replaced the most similar sequence within the OmpA, and three validated epitopes of OmpA were retained intact. The obtained antigen encompasses five antigenic peptides of spike protein, which are involved in SARS-CoV-2 pathogenicity. One of these epitopes, viz. QTQTNSPRRARSV could trigger antibodies preventing super-antigenic characteristics of spike and alleviating probable autoimmune responses. The designed antigen could raise antibodies neutralizing emerging variants of SARS-CoV-2 since at least two epitopes are consensus. In conclusion, the designed antigen is expected to raise protective antibodies against SARS-CoV-2, A. baumannii, and P. aeruginosa.

Pierce into Structural Changes of Interactions Between Mutated Spike Glycoproteins and ACE2 to Evaluate Its Potential Biological and Therapeutic Consequences.

The structural consequences of ongoing mutations on the SARS-CoV-2 spike-protein remains to be fully elucidated. These mutations could change the binding affinity between the virus and its target cell. Moreover, obtaining new mutations would also change the therapeutic efficacy of the designed drug candidates. To evaluate these consequences, 3D structure of a mutant spike protein was predicted and checked for stability, cavity sites, and residue depth. The docking analyses were performed between the 3D model of the mutated spike protein and the ACE2 protein and an engineered therapeutic ACE2 against COVID-19. The obtained results revealed that the N501Y substitution has altered the interaction orientation, augmented the number of interface bonds, and increased the affinity against the ACE2. On the other hand, the P681H mutation contributed to the increased cavity size and relatively higher residue depth. The binding affinity between the engineered therapeutic ACE2 and the mutant spike was significantly higher with a distinguished binding orientation. It could be concluded that the mutant spike protein increased the affinity, preserved the location, changed the orientation, and altered the interface amino acids of its interaction with both the ACE2 and its therapeutic engineered version. The obtained results corroborate the more aggressive nature of mutated SARS-CoV-2 due to their higher binding affinity. Moreover, designed ACe2-baased therapeutics would be still highly effective against covid-19, which could be the result of conserved nature of cellular ACE2. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10989-021-10346-1.

Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies.

Rheumatoid arthritis (RA) is considered a chronic systemic, multi-factorial, inflammatory, and progressive autoimmune disease affecting many people worldwide. While patients show very individual courses of disease, with RA focusing on the musculoskeletal system, joints are often severely affected, leading to local inflammation, cartilage destruction, and bone erosion. To prevent joint damage and physical disability as one of many symptoms of RA, early diagnosis is critical. Auto-antibodies play a pivotal clinical role in patients with systemic RA. As biomarkers, they could help to make a more efficient diagnosis, prognosis, and treatment decision. Besides auto-antibodies, several other factors are involved in the progression of RA, such as epigenetic alterations, post-translational modifications, glycosylation, autophagy, and T-cells. Understanding the interplay between these factors would contribute to a deeper insight into the causes, mechanisms, progression, and treatment of the disease. In this review, the latest RA research findings are discussed to better understand the pathogenesis, and finally, treatment strategies for RA therapy are presented, including both conventional approaches and new methods that have been developed in recent years or are currently under investigation.

Anticancer Effects of Herbal Medicine Compounds and Novel Formulations: a Literature Review.

INTRODUCTION: Many agents disrupt the cell cycle and its signaling circuits leading to cancer progress. Cancer therapy is performed by surgery, radiation, and chemical drugs remaining some side effects. OBJECTIVE: To evaluate the anticancer traits of herbal medicines. METHODS: We collected previously published data in searching engines (Web of Science, PubMed, Medline, and SCOPUS) by searching key words "herbal medicine," "anticancer effect," "compounds," and "fractions." RESULTS: Herbal medicines have unraveled anticancer effects mostly through cancer cells apoptosis via blocking NF-κB pathway by curcumin and terpenoides; CD95 signaling and enhancement of CD95L expression by resveratrol; and inhibiting tyrosine kinas, angiogenesis, and cell cycle arrest in G2/M phase by ß-lapachone-genistein and cytochrome-c release into the cytosol and caspase-9 activation by biocalein and quercetin. Additionally, impeding cell cycle in the G1 phase in ovarian cancer cells by 7-hydroxystaurosporine, immune cells enrichment (neutrophils and NK cells activation by Viscum album L., T cells and NK cells activation and cytokines such as tumor necrosis factor release by Ganoderma lucidum and microRNAs regulation (by Sinomeniumacutum, shikonin, Oleaeuropaea, curcumin and ginseng). These effects have implications for proper cancer cells elimination. It has been revealed that cytotoxic effects of herbal compounds (mostly those secondary metabolites) have exerted anticancer properties against several cancer cell lines. In addition, targeting microRNAs, nanoparticle-assisted herbal synergism, and novel drug delivery systems and combination chemotherapies have also emerged exerting higher efficacies for specific cell targeting as novel cancer therapy approaches. CONCLUSION: Considering side effects, toxicity, and higher costs of common cancer therapy approaches, application of novel herbal medicine-based therapies will confer promising insights for health outcomes.

Point mutation detection by economic HRM protocol primer design.

Globally more than 100 million SNPs in populations. These variations approximately 4-5 million SNPs in a people genome, occur almost every 1000 nucleotides on average and present either unique or in many in individuals. They can act as genetic signs, associated with illness and respond to chemicals and drugs. SNPs occurrence within or near a gene play important role in disease throughout affecting gene task. Frequently many protocols have been used to study single nucleotide polymorphism (SNP) among human variants genome. Restriction fragment length polymorphism (RFLP), Amplification refractory mutation system PCR(ARMS-PCR), sequencing and SNaPshot assays considered familial methods. The potential risk of contamination after PCR is common due to further other steps. In this direction, a high resolution melting (HRM) real-time PCR method is an alternative, reducing the post-PCR transferring steps. uVariants is clarified as appropriate website for designing primers used for SNP recognition by easy and inexpensive protocol called HRM. The researchers can focus on the interest of reference SNP ID number, or "rs" ID to avoid loss time. In this article description how to uses uVariants website for primer design used in HRM technique. AIMS: To describe uVariants and uDesign software, application and usefulness of HRM technique primer design in the genotyping SNPs among people and public health. ACCESSIBILITY AND REQUIREMENTS: uVariants and uDesign are freely accessible at: https://www.dna.utah.edu/variants/;https://www.dna.utah.edu/udesign/app.php respectively.The network server supports the browsers: Chrome, Firefox, Torch, CoolNovo, 360 Browser, Internet Explorer, Opera, and Safari.

Retraction notice to 'Point mutation detection by economic HRM protocol primer design '[Biochem. Biophys. Rep. 18 (2019) 100628].

[This retracts the article DOI: 10.1016/j.bbrep.2019.100628.].