Current Topics in Medicinal Chemistry - Volume 17, Issue 20, 2017

Protein kinases are one of the most targeted protein families in current drug discovery pipelines. They are implicated in many oncological, inflammatory, CNS-related and other clinical indications. Virtual screening is a computational technique with a diverse set of available tools that has been shown many times to provide novel starting points for kinase-directed drug discovery. This review starts with a concise overview of the function, structural features and inhibitory mechanisms of protein kinases. In addition to briefly reviewing the practical aspects of structure-based virtual screenings, we discuss several case studies to illustrate the state of the art in the virtual screening for type I, type II, allosteric (type III-V) and covalent (type VI) kinase inhibitors. With this review, we strive to provide a summary of the latest advances in the structure-based discovery of novel kinase inhibitors, as well as a practical tool to anyone who wishes to embark on such an endeavor.

Fragment-based drug discovery (FBDD) is a broadly used strategy in structure-guided ligand design, whereby low-molecular weight hits move from lead-like to drug-like compounds. Over the past 15 years, an increasingly important role of the integration of these strategies into industrial and academic research platforms has been successfully established, allowing outstanding contributions to drug discovery. One important factor for the current prominence of FBDD is the better coverage of the chemical space provided by fragment-like libraries. The development of the field relies on two features: (i) the growing number of structurally characterized drug targets and (ii) the enormous chemical diversity available for experimental and virtual screenings. Indeed, fragment-based campaigns have contributed to address major challenges in lead optimization, such as the appropriate physicochemical profile of clinical candidates. This perspective paper outlines the usefulness and applications of FBDD approaches in medicinal chemistry and drug design.

Prevention and treatment of influenza virus infection is an ongoing unmet medical need. Each year, thousands of deaths and millions of hospitalizations are attributed to influenza virus infection, which poses a tremendous health and economic burden to the society. Aside from the annual influenza season, influenza viruses also lead to occasional influenza pandemics as a result of emerging or re-emerging influenza strains. Influenza viruses are RNA viruses that exist in quasispecies, meaning that they have a very diverse genetic background. Such a feature creates a grand challenge in devising therapeutic intervention strategies to inhibit influenza virus replication, as a single agent might not be able to inhibit all influenza virus strains. Both classes of currently approved anti-influenza drugs have limitations: the M2 channel blockers amantadine and rimantadine are no longer recommended for use in the U.S. due to predominant drug resistance, and resistance to the neuraminidase inhibitor oseltamivir is continuously on the rise. In pursuing the next generation of antiviral drugs with broad-spectrum activity and higher genetic barrier of drug resistance, the influenza virus nucleoprotein (NP) stands out as a high-profile drug target. This review summarizes recent developments in designing inhibitors targeting influenza NP and their mechanisms of action.

Designing new vaccines is one of the most challenging tasks for public health to prevent both infectious and chronic diseases. Even though many research scientists have spent great efforts in improving the specificity, sensitivity and safety of current available vaccines, there are still much space on how to effectively combine different biomaterials and technologies to design universal or personalized vaccines. Traditionally, vaccines were made based on empirical approaches designed to mimic immunity induced by natural infection. Either live attenuated or killed whole microorganisms were used as vaccines. With the development of biomaterial science, DNA/RNA, recombinant vector, adjuvant and nanoparticles greatly expand the category of vaccines. More importantly, with the tremendous advances of new technologies including genomics, proteomics and immunomics, the paradigm of vaccine design has shifted from microbiological to sequence-based approaches. This ever-growing large amount of genomic data and new genomic approaches such as comparative genomics, reverse vaccinology and pan-genomics, will play critical roles in novel vaccine design and enable development of more effective vaccines to cure and control both chronic and infectious diseases. In this review, we summarize current various vaccine materials, advanced technologies and combinational strategies to integrate biomaterials and advanced technologies for vaccine design, which we hope will provide some very useful guidelines and perspectives for the vaccine design.

Cyclic peptides, owing to their good stability, high resistance to exo- and to some extent endo-peptidases, enhanced binding affinity and selectivity towards target biomolecules, are actively investigated as biochemical tools and therapeutic agents. In this review, we discuss various commonly utilized synthetic strategies for cyclic peptides and peptoids (peptidomimetics), their important screening methods to identify the bioactive cyclic peptides and peptoids such as combinatorial beadbased peptide library, phage display, mRNA display etc. and recent advances in their applications as bioactive compounds. Lastly, we also make a summary and provide an outlook of the research area.

Nanocarriers are widely used for delivering drugs to tumors and are progressing in a stable trend, because malignant tumors remain a major health burden throughout the world and effective therapeutic strategies are urgently needed. Furthermore, as an integrated platform, nanocarriers have the potential to dramatically improve cancer diagnosis, imaging, and therapy, while reducing the toxicity associated with the current approaches. Significantly, intelligent nanocarriers are the new generation of the nanocarriers, exhibiting superior tumor targeting and improved therapeutic efficacy. In this review, we discuss recent development in the design of nanoscale stimuli-responsive systems which will be able to control drug biodistribution in response to specific stimuli, either exogenous or endogenous. Meanwhile, the recent progress in engineering intelligent and versatile nanomaterials for targeting the tumor microenvironment is summarized.