Original article Characteristics of known drug space. Natural products, their derivatives and synthetic drugs Richard Bade, Ho-Fung Chan, Jóhannes Reynisson * Department of Chemistry, Auckland Bioengineering Institute, The University of Auckland, Auckland 1142, New Zealand article info Article history: Received 9 July 2010 Received in revised form 1 September 2010 Accepted 8 September 2010 Available online 17 September 2010 Keywords: Known drug space Marketed drug compounds Drug-like chemical space Natural products Natural derivatives Semi-synthetic drugs Synthetic drugs Molecular descriptors and drug development/discovery abstract Known drug space (KDS) was analysed for the occurrence of natural products and their derivatives. A database of 1000 marketed drugs was compiled. It was found that 10% of the drugs on the market are unaltered natural products, 29% are their derivatives (semi-synthetics) and the rest (61%) have a synthetic origin. Of the natural products, and their derivatives, polycyclic drugs were the most abun- dant at 21% followed by simple drugs (16%) and steroids (15%). In regard to the molecular descriptors the natural products had larger statistical means and standard deviations than their synthetic counterparts. It was found that KDS occupies a larger volume in chemical space with respect to drug-like chemicals, i.e., KDS fully encompasses drug-like chemical space with the parameters of molecular weight  800 g mol 1 , log P  6.5, hydrogen bond acceptors  15, hydrogen bond donors  7, polar surface area  180  A 2 , and rotatable bonds  17. Only 13% of the drugs analysed are outside one or more of these parameters. The definition of KDS gives drug designers a larger volume to work in compared to drug-like chemical space. However, the bulk of known drugs are found within the volume of drug-like chemical space. Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction The concept of drug-like chemical space is widely used in the development and selection of drug candidates [1]. Drug-like chemical space is defined as those compounds that have pharma- cokinetic properties to survive the completion of human phase I clinical trials [2]. The most common criteria for drug-like chemical space are the Lipinski’s rule of five, which has gained widespread popularity [3,4]. Topological polar surface area (TPSA) and rotatable bonds are also widely used as molecular descriptors [5e7]. In addition to molecular descriptors, molecular moieties, known to perturb biochemical and cell based assays generating false posi- tives, are also used to eliminate molecules from drug-like chemical space [8e12]. This definition of drug-like chemical space is depic- ted graphically in Fig. 1 . Known drug space (KDS) is a related concept to drug-like chemical space [13,14]. KDS incorporates all small molecules currently marketed based on the idea that compounds that have passed clinical trials and stay in medical use have acceptable pharmacokinetic profiles. This is obviously a broad generalisation however it is a simple concept and can be applied to test hypothesis and ideas in the framework of drug discovery. E.g., KDS has been used to test whether certain moieties and atoms should be included in compound screening collections and for the qualitative testing of global QSAR models [13e15]. Moreover, an interesting use of known drugs was recently published defining biomolecular targets by its ligands (drugs) [16]. Furthermore, natural product drugs have been used for a bioinformatic analysis of protein targets implicated in human disease [17]. KDS is a new concept and we hope with this investigation to put it on a solid theoretical foundation for the use in drug discovery. It is well known that marketing drugs nowadays is more difficult than previously due to stricter regulations indicating that some older drugs do not have acceptable pharmacokinetic profiles (see Ref. [18] and references therein). However, using marketed drugs as a reference in chemical space is a very attractive concept since these compounds are used clinically every day by millions of people extending and improving their lives. Furthermore, serendipity has played a major role in the discovery and development of drugs and by using KDS this poorly understood yet important phenomenon is included [19,20]. It is reasonable to assume that KDS is larger than drug-like chemical space since there are classes of drugs which lie outside of * Corresponding author. Department of Chemistry, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Tel.: þ64 9 373 7599x83746; fax: þ64 9 373 7422. E-mail address: j.reynisson@auckland.ac.nz (J. Reynisson). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.09.018 European Journal of Medicinal Chemistry 45 (2010) 5646e5652