CHEM 4315/6315

For the past decade, the number of molecular targets for approved drugs has been debated. Here, we reconcile apparently contradictory previous reports into a comprehensive survey, and propose a consensus number of current drug targets for all classes of approved therapeutic drugs. One striking feature is the relatively constant historical rate of target innovation (the rate at which drugs against new targets are launched); however, the rate of developing drugs against new families is significantly lower. The recent approval of drugs that target protein kinases highlights two additional trends: an emerging realization of the importance of polypharmacology, and also the power of a gene-family-led approach in generating novel and important therapies.

The evolution that has taken place in medicinal chemistry practice as a result of major advances in genomics and molecular biology arising from the Human Genome Project has carried with it an extensive additional working vocabulary that has become both integrated and essential terminology for the medicinal chemist. Some of this augmented terminology has been adopted from the many related and interlocked scientific disciplines with which the modern medicinal chemist must be conversant, but many other terms have been introduced to define new concepts and ideas as they have arisen. In this supplementary Glossary, we have attempted to collate and define many of the additional terms that are now considered to be essential components of the medicinal chemist’s expanded repertoire.

MicroRNAs (miRNAs) are small non-coding RNAs with a length of about 19–25 nt, which can regulate various target genes and are thus involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. Drug resistance in cancer chemotherapy is one of the main obstacles to curing this malignant disease. Statistical data indicate that over 90% of the mortality of patients with cancer is related to drug resistance. Drug resistance of cancer chemotherapy can be caused by many mechanisms, such as decreased antitumor drug uptake, modified drug targets, altered cell cycle checkpoints, or increased DNA damage repair, among others. In recent years, many studies have shown that miRNAs are involved in the drug resistance of tumor cells by targeting drug-resistance-related genes or influencing genes related to cell proliferation, cell cycle, and apoptosis. A single miRNA often targets a number of genes, and its regulatory effect is tissue-specific. In this review, we emphasize the miRNAs that are involved in the regulation of drug resistance among different cancers and probe the mechanisms of the deregulated expression of miRNAs. The molecular targets of miRNAs and their underlying signaling pathways are also explored comprehensively. A holistic understanding of the functions of miRNAs in drug resistance will help us develop better strategies to regulate them efficiently and will finally pave the way toward better translation of miRNAs into clinics, developing them into a promising approach in cancer therapy.

The advent of multidrug resistance among pathogenic bacteria is imperiling the worth of antibiotics, which have previously transformed medical sciences. The crisis of antimicrobial resistance has been ascribed to the misuse of these agents and due to unavailability of newer drugs attributable to exigent regulatory requirements and reduced financial inducements. Comprehensive efforts are needed to minimize the pace of resistance by studying emergent microorganisms, resistance mechanisms, and antimicrobial agents. Multidisciplinary approaches are required across health care settings as well as environment and agriculture sectors. Progressive alternate approaches including probiotics, antibodies, and vaccines have shown promising results in trials that suggest the role of these alternatives as preventive or adjunct therapies in future. Keywords: antibiotics, multidrug resistance, evolution, alternative therapies

Ovarian cancer is the most lethal malignancy among the gynecological cancers, with a 5‐year survival rate, mainly due to being diagnosed at advanced stages, recurrence and resistance to the current chemotherapeutic agents. Drug resistance is a complex phenomenon and the number of known involved genes and cross‐talks between signaling pathways in this process is growing rapidly. Thus, discovering and understanding the underlying molecular mechanisms involved in chemo‐resistance are crucial for management of treatment and identifying novel and effective drug targets as well as drug discovery to improve therapeutic outcomes. In this review, the major and recently identified molecular mechanisms of drug resistance in ovarian cancer from relevant literature have been investigated. In the final section of the paper, new approaches for studying detailed mechanisms of chemo‐resistance have been briefly discussed.

For the planning of an organic synthesis route, the disconnection approach guided by retrosynthetic analysis of possible intermediates and the chemical reactions involved, back to ready available starting materials, is well established. In contrast, such concepts just get developed for biocatalytic routes. In this Review we highlight functional group interconversions catalyzed by enzymes. The article is organized rather by chemical bonds formed—exemplified for C−N, C−O‐ and C−C‐bonds—and not by enzyme classes, covering a broad range of reactions to incorporate the desired functionality in the target molecule. Furthermore, the successful use of biocatalysts, also in combination with chemical steps, is exemplified for the synthesis of various drugs and advanced pharmaceutical intermediates such as Crispine A, Sitagliptin and Atorvastatin. This Review also provides some basic guidelines to choose the most appropriate enzyme for a targeted reaction keeping in mind aspects like commercial availability, cofactor‐requirement, solvent tolerance, use of isolated enzymes or whole cell recombinant microorganisms aiming to assist organic chemists in the use of enzymes for synthetic applications. Biocatalysis: This Review highlights retrosynthesis concepts using enzymes as biocatalysts exemplified for C−N, C−O and C−C bond formations. Furthermore, a range of examples for the combination of biocatalysis with chemical reactions is illustrated for the synthesis of drugs and APIs such as Crispine A, Sitagliptin or Atorvastatin. Basic guidelines are provided as to how to choose the most appropiate enzyme for a targeted reaction.

DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chemistry enables the exploration of chemical spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technology requires developing a range of capabilities including aqueous synthetic chemistry, building block acquisition, oligonucleotide conjugation, large-scale molecular biological transformations, selection methodologies, PCR, sequencing, sequence data analysis and the analysis of large chemistry spaces. This Review provides an overview of the development and applications of DNA-encoded chemistry, highlighting the challenges and future directions for the use of this technology.