Current Medicinal Chemistry - Volume 28, Issue 34, 2021

Enveloped viruses belong to a large class of pathogens responsible for multiple serious diseases. Their spread into new territories has been the cause of major epidemics throughout human history, including the Spanish flu in 1918 and the latest COVID-19 pandemic. Thanks to their outer membrane, consisting essentially of host lipids, enveloped viruses are more resistant to enzymes and are also less susceptible to host immune defenses than their naked counterparts. Therefore, the development of effective approaches to combat enveloped virus infections represents a major challenge for antiviral therapy in the current century. This review focuses on the characteristics of enveloped viruses, their importance in the entry phase, drugs targeting envelope membrane- mediated entry, and those specifically designed to target the envelope. The broad- -spectrum antiviral activity of these compounds can be attributed to their ability to affect the envelope, an essential structural feature common to several viruses. This makes this class of compounds agents of great interest when no specific drugs or vaccines are available to block viral infections.

Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase involved in the process of cell proliferation, survival, migration, and invasion. It has become a promising therapeutic target for the treatment of human metastatic cancers due to its overexpression and/or activation in multiple cancer types. Since FAK is emerging as a potential cancer target because of its overexpression at both the transcriptional and translational level in cancer, different types of FAK inhibitors with diversified scaffolds have been discovered in the past few years. In this review, the progress of recently discovered small molecule FAK inhibitors was summarized. Major efforts have been focused on the rational design and synthesis of small molecule FAK inhibitors, and their structure-activity relationship (SAR) analysis wasalso discussed. Among them, while type I inhibitors remain as the major focuses, type II inhibitors and novel allosteric FAK inhibitors (type III inhibitors) have been developed to improve both potency and selectivity. Meanwhile, novel strategies, such as targeting FAK using inhibitors of protein-protein interactions, were also discovered. Lastly, some insights and perspectives on the future development of FAK inhibitors as anticancer therapeutics have been provided.

As a new type of nanomaterials, the gold nanoclusters (AuNCs) perform many special physical and chemical properties, such as large Stokes shift, relatively simple preparation, good water solubility, low toxicity, and good biocompatibility, which make them show infinite potential in various fields, especially in cancer treatment. In recent years, great progress has been made in the preparation, functionalization, and biomedical applications of the AuNCs. In this article, the latest research progress and synthesis methods of the AuNCs have been summarized, emphasizing the preparation using the “bottom- up” synthesis strategy. Furthermore, we introduced the in vivo pharmacokinetic performance of the AuNCs. In the last part, we exemplified the applications of the AuNCs in biomedicine, including photothermal therapy (PTT), bioimaging, drug delivery, and radiotherapy sensitization, which further confirmed the great potential of the AuNCs in tumor treatment.

Background: One of the main challenges in the early stages of drug discovery is the computational assessment of protein-ligand binding affinity. Machine learning techniques can contribute to predicting this type of interaction. We may apply these techniques following two approaches. Firstly, using the experimental structures for which affinity data is available. Secondly, using protein-ligand docking simulations. Objective: In this review, we describe recently published machine learning models based on crystal structures, for which binding affinity and thermodynamic data are available. Method: We used experimental structures available at the protein data bank and binding affinity and thermodynamic data was accessed through BindingDB, Binding MOAD, and PDBbind databases. We reviewed machine learning models to predict binding created using open source programs, such as SAnDReS and Taba. Results: Analysis of machine learning models trained against datasets, composed of crystal structure complexes indicated the high predictive performance of these models when compared with classical scoring functions. Conclusion: The rapid increase in the number of crystal structures of protein-ligand complexes created a favorable scenario for developing machine learning models to predict binding affinity. These models rely on experimental data from two sources, the structural and the affinity data. The combination of experimental data generates computational models that outperform the classical scoring functions.

Beyond being an excellent protective material for bioentities, zeolitic imidazolate frameworks (ZIF-8) have advanced several applications, including biomedical applications. The straightforward synthesis of ZIF-8 at mild conditions improved the biomineralization of several biomolecules, e.g., protein, peptides, carbohydrate, and biological cells, such as viruses and bacterial cells. Bioinspiration of ZIF-8 enhanced and improved the material's applications for biomedicine. This review article summarized the recent achievements of ZIF-8 for biomedical applications such as cancer therapy, antimicrobial, biosensing, and biocatalysis. ZIF8-based materials advanced cancer therapy via drug delivery of chemotherapeutic drugs, photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), gene therapy, and starvation therapy. Antibacterial agent encapsulated ZIF-8 exhibited superior biological activity compared to the free antibacterial agents. ZIF-8 based materials enhanced the selectivity and sensitivity for analytes' biosensing, ensuring their potential for electronic devices. Biocatalysis of enzyme encapsulated ZIF-8 offered high catalytic performance with robust properties for recycling. ZIF-8 acts as a protective host for enzymes, proteins, and drugs from degradation induced due to temperature, solvents, and proteolytic agents. The first part of the review discussed the structure, chemistry, and bioinspiration of ZIF-8. The second part reviewed the biomedical applications of ZIF-8. The potential risks and current challenges of using ZIF-8 for biomedical applications were also reviewed.

Nucleobases represent key structural motifs in biologically active molecules, including synthetic and natural products. Molecular modifications made on nucleobases or their isolation from natural sources are being widely investigated for the development of drugs with improved potency for the treatment of different diseases, such as cancer, as well as viral and bacterial infections. This review article focuses on the nucleobase analogue drug developments of the past 20 years (2000-2020). Various pharmacological and medicinal aspects of nucleobases and their analogues are discussed. The current state and limitations are also highlighted.

Curcumin, a yellow pigment in Asian spice, is a natural polyphenol component of Curcuma longa rhizome. Curcuminoid components include curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Previous studies established curcumin as a safe agent based on preclinical and clinical evaluations and curcuminoids have been approved by the US Food and Drug Administration (FDA) as “Generally Recognized as Safe” (GRAS). The present review collects and summarizes clinical and preclinical studies of curcumin interactions, with an emphasis on the effect of curcumin and curcumin analogs on the mRNA and protein levels of microsomal CYP450 enzymes (phase I metabolism) and their interactions with toxicants, drugs and drug probes. The literature search was conducted using keywords in various scientific databases, including Web of Science, Scopus, PubMed, and Google Scholar. Studies concerning the impact of curcumin and curcumin analogs on microsomal enzyme activity are reviewed and include oral, topical, and systemic treatment in humans and experimental animals, as well as studies from in vitro research. When taken together, the data identified some inconsistent results between various studies. The findings showed significant inhibition of CYP450 enzymes by curcumin and its analogs. However, such effects are often differed when curcumin and curcumin analogs were coadministered with toxicant and other drugs and drug probes. We conclude from this review that herb-drug interactions should be considered when curcumin and curcumin analogs are consumed.

Autism Spectrum Disorder (ASD) is a disorder with different etiologies and poor elucidation, characterized by changes in social and cognitive skills. ASD impacts a large number of people in the world. Surprisingly, in spite of its great importance, just modest progress has been achieved towards comprehending this pathology and designing new therapies. The molecular dysfunctions observed in people with autism are evidenced by the interference in the synthesis of synaptic proteins, which impairs their development and plasticity, leading to characteristics of individuals with ASD. The present work investigates the mTOR pathway and the proteins related to its regulation and neurological functioning. The path of protein synthesis and translation is promising to treat various disorders and its elucidation may, for example, result in drugs that facilitate the diagnosis and broaden the range of treatments, improving the quality of life of ASD patients.

Objective: This review aims to study the receptor's family and functions most related to COVID-19 infection and also suggest the tissue and cell location on which the majority of COVID-19 receptors are mainly expressed. Methods: This systematic review is according to PRISMA guidelines. PubMed, Cochrane, SciELO, Lilacs, Web of Science, and DOAJ databases were used. Clinical trials and research articles studying receptors related to COVID-19 were included in this review. R programming language was used to elaborate charts and receptors network, and SPSS(26v) software was used to perform statistical analysis (PROSPERO: CRD42020210643). Results: The majority of studies on the involvement of receptors in COVID-19 included plasma receptors and G protein-coupled receptor families (p<0.05). These receptors are highly expressed in the brain (24%) and 80% of them can interact with each other in a protein network, exerting some regulatory effects on various tissues. The main influential receptor in the network of receptors involved in the COVID-19 was the EGFR and the majority of receptors were associated with pathological processes of the disease (p<0.05), including the amplification of inflammatory responses in COVID-19, which may be related to neurological disorders in some cases. Studies on receptors involved in the COVID-19 included mainly patients from the United States, Spain, and Brazil (p<0.05). Conclusion: Plasma receptors and G protein-coupled receptors, especially the EGFR, involved in pathological effects of the COVID-19 inflammatory process in the brain have shown significant importance in this review.