Plant natural fragments, an innovative approach for drug discovery
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Plant natural fragments, an innovative approach for drug discovery Bruno David Denis Zeyer
. Antonio Grondin . Philippe Schambel . Marc Vitorino .
Received: 7 February 2019 / Accepted: 21 May 2019 Ó Springer Nature B.V. 2019
Abstract Plant natural products (PNP) (e.g., secondary vegetal metabolites and their derivatives) have been a productive source of active ingredients for the pharmaceutical industry. The High Throughput Screening of Plant Natural Products (PNP-HTS) with extracts or isolated compounds has shown to be time consuming, expensive, and not as successful as expected. Recently building upon the innovative fragment-based drug discovery (FBDD) a disruptive approach was developed based on PNP. The fragment approach involves elaboration and/or isolation of weakly binding small molecules with molecular weights between 150 and 250 Da. This method is fundamentally different from HTS in almost every aspect (i.e., size of the compound library, screening methods, and optimization steps from hit to lead). Due to their nature, vegetal natural fragments have unique three-dimensional (3D) properties, high Fsp3, low aromaticity, and large chemo-diversities which represent potential opportunities for developing novel drugs. Preliminary results using vegetal natural fragments appear to be a promising and emerging field B. David (&) A. Grondin P. Schambel Poˆles Actifs Ve´ge´taux et Chemoinformatique, Institut de Recherche Pierre Fabre, 3, Avenue Hubert Curien, BP 13562, 31562 Toulouse, France e-mail: [email protected] M. Vitorino D. Zeyer NovAliX, 850, Boulevard Se´bastien Brant, BP 30170, 67405 Illkirch, France
which offers valuable prospects for developing new drugs. Keywords Fragment Drug discovery Fragmentbased drug discovery Ligand efficiency Abbreviations ADMET Administration–distribution– metabolization–excretion–toxicology studies FBDD Fragment based drug discovery Fsp3 Ratio of sp3 carbon to the total number of carbon HTS High throughput screening MS Mass spectrometry NMR Nuclear magnetic resonance NP Natural products PF Pierre Fabre PFL Plant fragment library PNP Plant natural products SPR Surface plasmon resonance
Introduction In the last few decades, productivity of research and development in the pharmaceutical industry has been declining despite huge scientific, technological, and organizational advances coupled with dramatically
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increasing costs of research and development (R&D) of new drugs (Scannel et al. 2012). Plant natural products (PNP) are an indisputably valuable source of structural and functional diversity, but, have dwindled in usage in the pharmaceutical industry (David et al. 2015). Bioprospection and screening of PNP was largely performed between 1990 and 2005, when large pharmaceutical corporations were conducting PNP-HTS drug discovery programmes (Butler et al. 2014). Strategy is the most important feature of a drug discovery programme, and as such, the industry has employed different successi
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