Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

/pdf/the-re-emergence-of-natural-products-for-drug-discovery-in-1h0jebzmkp.pdf

The re-emergence of natural products for drug discovery in the genomics era

The pharmaceutical industry is progressively operating in an era where development costs are constantly under pressure, higher percentages of drugs are demanded, and the drug-discovery process is a trial-and-error run. The profit that flows in with the discovery of new drugs has always been the motivation for the industry to keep up the pace and keep abreast with the endless demand for medicines. The process of finding a molecule that binds to the target protein using in silico tools has made computational chemistry a valuable tool in drug discovery in both academic research and pharmaceutical industry. However, the complexity of many protein-ligand interactions challenges the accuracy and efficiency of the commonly used empirical methods. The usefulness of quantum mechanics (QM) in drug-protein interaction cannot be overemphasized; however, this approach has little significance in some empirical methods. In this review, we discuss recent developments in, and application of, QM to medically relevant biomolecules. We critically discuss the different types of QM-based methods and their proposed application to incorporating them into drug-design and -discovery workflows while trying to answer a critical question: are QM-based methods of real help in drug-design and -discovery research and industry?

/pdf/quantum-mechanics-implementation-in-drug-design-workflows-1ci7qwppwn.pdf

Quantum mechanics implementation in drug-design workflows: does it really help?

Engagement of phytoestrogens in breast cancer suppression: Structural classification and mechanistic approach

Lasso peptides, a peculiar family of ribosomally assembled and post-translationally modified peptides (RiPPs), possess a fascinating 3D structure, which can confer rigidity and stability against chemical and thermal denaturation. Their distinctive “lariat knot” structure is accountable for their antibacterial, enzyme inhibitory and receptor antagonist activities. While the biosynthetic machinery was recently characterized, the rules concerning the formation of this unique lasso structure on the basis of their peptide sequences remain elusive. Restrictions such as the length of the peptide, the size of the ring, or the nature of the amino acids associated with the lasso fold stabilization were recently overhauled by the identification of new members of this RiPP family. In this work we demonstrate the isolation of four genome-mining-predicted lasso peptides featuring the unprecedented amino acids serine or alanine at position 1 of the core peptide. By a mutational approach we were able to predict the lasso fold for four peptides (caulonodins IV to VII). This prediction was confirmed for caulonodin V by the full elucidation of its 3D-structure via NMR and for caulonodin VI by the determination of long range NOE-contacts. Furthermore, the substrate specificity of the biosynthetic machinery for the atypical position 1 was probed. Additionally, utilizing the recent growth of functional lasso peptide precursor sequences we were able to identify a conserved motif in the C-terminal part of the leader peptide through bioinformatics analysis. Employing an extensive in vivo analysis for substitution tolerance of the biosynthetic machinery in this conserved region confirmed the significance of several residues, indicating that the predicted motif is very likely a general leader peptide recognition sequence specific for lasso peptide maturation.

https://pubs.rsc.org/en/content/articlepdf/2014/SC/C4SC01428F

Characterization of caulonodin lasso peptides revealed unprecedented N-terminal residues and a precursor motif essential for peptide maturation

The RNA-binding protein Musashi-1 (MSI1) promotes stemness during development and cancer. By controlling target mRNA turnover and translation, MSI1 is implicated in the regulation of cancer hallmarks such as cell cycle or Notch signaling. Thereby, the protein enhanced cancer growth and therapy resistance to standard regimes. Due to its specific expression pattern and diverse functions, MSI1 represents an interesting target for cancer therapy in the future. In this review we summarize previous findings on MSI1's implications in developmental processes of other organisms. We revisit MSI1's expression in a set of solid cancers, describe mechanistic details and implications in MSI1 associated cancer hallmark pathways and highlight current research in drug development identifying the first MSI1-directed inhibitors with anti-tumor activity.

https://www.mdpi.com/2079-7737/10/5/407/pdf

Musashi–1—A Stemness RBP for Cancer Therapy?

Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specificpromoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.

/pdf/selected-approaches-for-rational-drug-design-and-high-2yc0brpsjs.pdf

Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules

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Selected Approaches for Rational Drug Design and High Throughput Screening to Identify Anti-Cancer Molecules