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

Natural products in drug discovery.

Natural products and their molecular frameworks have a long tradition as valuable starting points for medicinal chemistry and drug discovery. Recently, there has been a revitalization of interest in the inclusion of these chemotypes in compound collections for screening and achieving selective target modulation. Here we discuss natural-product-inspired drug discovery with a focus on recent advances in the design of synthetically tractable small molecules that mimic nature's chemistry. We highlight the potential of innovative computational tools in processing structurally complex natural products to predict their macromolecular targets and attempt to forecast the role that natural-product-derived fragments and fragment-like natural products will play in next-generation drug discovery.

Counting on natural products for drug design

The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of “active compound” has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of ‘organ-on chip’ and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug development. This review discusses plant-based natural product drug discovery and how innovative technologies play a role in next-generation drug discovery.

https://www.mdpi.com/1422-0067/19/6/1578/pdf/1

Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery.

Biologically active molecules can be identified through the screening of small-molecule libraries. Deficiencies in current compound collections are evidenced by the continuing decline in drug-discovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds. A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis (DOS) aims to generate such structural diversity in an efficient manner. Recent years have witnessed significant achievements in the field, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.

/pdf/diversity-oriented-synthesis-as-a-tool-for-the-discovery-of-clriq0tput.pdf

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Scaffold diversity of natural products: inspiration for combinatorial library design

Computer-based analysis revealed that natural products exhibit a remarkable structural diversity of molecular frameworks and scaffolds that could be systematically exploited for combinatorial synthesis. Natural products offer a rich pool of unique molecular frameworks that complement "drug space". They possess desirable druglike properties rendering them ideal starting points for molecular design considerations. This review provides an overview of chemotype diversity and molecular properties of collections of drugs and druglike molecules, pure natural products, and natural product- derived compounds. Compared to druglike molecules, pure natural products contain more oxygen atoms and chiral cen- ters, and have less aromatic atoms on average. Among the natural product library we identified more than one thousand scaffolds that were not contained in any other compound set analyzed. This outcome provides a basis for the design of new natural product-derived compound libraries. Our study demonstrates that computational chemical biology can assist in finding suitable molecular entities in collections of natural products for drug discovery.

Properties and Architecture of Drugs and Natural Products Revisited

Ideally, a novel lead structure represents a different chemotype from known ligands of a given target macromolecule. Virtual screening techniques and molecular de novo design are able to perform “scaffold-hopping”, and can thus be used as idea generators for medicinal chemistry. The task is to find isofunctional bioactive molecules with different backbone architectures. Here, we present the successful application of our “fuzzy” pharmacophore method LIQUID (“ligand-based quantification of interaction distributions”) to finding novel RNA ligand scaffolds and new inhibitors of in vitro protein expression. LIQUID is akin to our previously introduced SQUID approach. Both techniques model pharmacophoric features as Gaussian densities. While SQUID operates with univariate distributions, LIQUID employs trivariate models. In a retrospective virtual-screening study, we first compared LIQUID and SQUID, which both work on 3D pharmacophores, with the corresponding 2D CATS approach. All three methods encode pharmacophoric information as a correlation vector; this allows for rapid alignment-free similarity searching (by pair-wise Euclidian distance) in large compound libraries. We assessed their ability to retrieve known ligands of six drug targets from a collection of drugs and lead compounds compiled from recent literature. Overall, the CATS 2D method outperformed the 3D methods in this study, and SQUID retrieved slightly more hits than LIQUID (Table 1). This outcome is not entirely surprising, as we employed only a single calculated conformation for each of the molecules, and owing to the fact that the trivariate pharmacophore points in the LIQUID models are more restrictive than their univariate counterparts in SQUID. Notably, within the error margins, all methods performed comparably and clearly demonstrated their ability to retrieve active species from a collection of drug-like compounds. As all targets employed for this preliminary retrospective assessment were proteins, we checked the scaffold-hopping abilities of SQUID and LIQUID by using an RNA target, namely the trans-activation response element (TAR) of human immunodeficiency virus (HIV) 1. AIDS is caused by infection with HIV, which belongs to the class of retroviruses. This viral class is able to transpose its genome and use the host’s replication machinery for proliferation. Regulatory viral units have been selected as targets for blocking viral replication. Specific interaction of TAR RNA with the Tat protein is essential for virus Table 1. Average enrichment of active species expressed as average enrichment factor <ef>=hitsfound/hitsexpected ( SD), yielded by retrospective virtual screening.

/pdf/scaffold-hopping-by-fuzzy-pharmacophores-and-its-application-m3aamj530n.pdf

Scaffold hopping by "fuzzy" pharmacophores and its application to RNA targets.

Natural products often contain scaffolds or core structures that prevent immediate synthetic accessibility. It is, therefore, desirable to find isosteric chemotypes that allow for scaffold-hopping ...

https://journals.sagepub.com/doi/pdf/10.1177/1934578X0800300821

Bioisosteric Replacement of Molecular Scaffolds: From Natural Products to Synthetic Compounds:

Natural products contain scaffold structures that can be systematically exploited for the design of combinatorial compound libraries with druglike properties. We review approaches for scaffold identification, and compare properties and pharmacophoric features of drugs and natural products. In particular, an application of the self-organizing map technique is presented for natural product-derived compound and library design.

Kristina Grabowski

Papers

Scaffold diversity of natural products: inspiration for combinatorial library design

Properties and Architecture of Drugs and Natural Products Revisited

Scaffold hopping by "fuzzy" pharmacophores and its application to RNA targets.

Bioisosteric Replacement of Molecular Scaffolds: From Natural Products to Synthetic Compounds:

Scaffold Diversity of Natural Products: Inspiration for Combinatorial Library Design