Various Dereplication Strategies Using LC-MS for Rapid Natural Product Lead Identification and Drug Discovery

Abstract

Natural products are the most consistently successful source of drug leads. The rapid identification of known compounds from natural product extracts, or 'dereplication', is an important step in an efficiently run drug discovery program. Modern spectroscopic methods have largely revolutionized compound identification and tremendously accelerated the pace at which isolated compounds can be identified. Dereplication strategies use analytical techniques and database searching to determine the identity of an active compound at the earliest possible stage in the discovery process. This prevents wasted effort on samples with no potential for development and allows resources to be focused on the most promising lead. In the past few years, advances in technology have allowed the development of tandem analytical techniques, such as HPLC-PDA, LC-MS, LC-MS-MS, LC-NMR, and LC-NMR-MS. This review describes the principles and performance of a number of hyphenated techniques involving LC-MS that can be used for dereplication of natural products for rapid lead identification.

A Historical Overview of Natural Products in Drug Discovery

“…Furthermore, even the selection of new types of organisms (terrestrial and/or marine) tends to lead to the rediscovery of previously reported natural products as they are often present in more than one phylum or genera [ 125 ]. It has been estimated that it takes $US 50,000 and three months of work to isolate and identify an active compound from a natural product source [ 126 ].…”

HPLC in Natural Product Analysis: The Detection Issue

“…Most of the API interfaces available cover ionisation of the vast majority of NPs, provided that correct conditions are used. Of course, the applications to NPs are manifold, and more details can be found in dedicated reviews [80], [82], [114], [115].…”

“…Furthermore, the use of tandem or hybrid MS instruments [80] provides in-depth structural information through fragmentation of the molecular species by CID reactions. Several reviews describe aspects related to online NP identification for screening and dereplication [82], [114], [115], [119], [136], for quality control, for fingerprinting for authentication or standardisation [80], or for the identification of biomarkers [137]. For online dereplication purposes, the determination of molecular weight is of great importance.…”

Gene Sequence Based Clustering Assists in Dereplication of Pseudoalteromonas luteoviolacea Strains with Identical Inhibitory Activity and Antibiotic Production

“…One of the main challenges in natural products discovery is the effort squandered rediscovering known compounds [ 16 ], hence so called “dereplication” strategies to reduce the degree of rediscovery prior to purification of compounds and structure elucidation steps are of outmost importance [ 17 , 18 , 19 ]. One such strategy is early stage dereplication informed by microbial systematics [ 20 , 21 , 22 ].…”