Available online at www.sciencedirect.com Environmental Toxicology and Pharmacology 25 (2008) 310–320 Aconitum and Delphinium alkaloids “Drug-likeness” descriptors related to toxic mode of action Malakhat A. Turabekova a,b , Bakhtiyor F. Rasulev b,∗ , Farkhad N. Dzhakhangirov b , Shavkat I. Salikhov a a Chemistry Department, National University of Uzbekistan named after Mirzo Ulugbek, Vuzgorodok, Tashkent 700174, Uzbekistan b Institute of Chemistry of Plant Substances, Kh. Abdullaev Str. 77, Tashkent 700170, Uzbekistan Received 3 April 2007; received in revised form 23 October 2007; accepted 23 October 2007 Available online 17 November 2007 Abstract Large series of Aconitum and Delphinium alkaloids have been investigated by means of QSAR analysis. Descriptors related to “drug-likeness” of molecules were selected to discriminate between “drugs” and “non-drugs” amongst diterpenoid alkaloids of interest. A usefulness of such approach has been assessed and it proved to give reliable results on whether a particular diterpenoid alkaloid is likely to be either poison or drug. A number of QSAR models with “drug-likeness” descriptors have also been obtained and discussed in terms of their relativity to the mode of toxic action exhibited by the alkaloids. The QSAR models were obtained with r value in the range 0.69–0.94. The q 2 (cross validation of r 2 ) values also confirm the statistical significance of our models. © 2007 Elsevier B.V. All rights reserved. Keywords: Alkaloids; Aconitum alkaloids; Delphinium alkaloids; QSAR; “Drug-likeness”; Toxicity 1. Introduction Diterpenoid alkaloids, found in plants of the genera Aconitum and Delphinium, have been the targets of considerable interest of medicinal chemists for a broad range of demonstrated pharma- cological properties: arrhythmogenic (neurocardiotoxic), local anesthetic, antiarrhythmic, curariform, analgesic, hypotensive, anti-inflammatory, spasmolytic, neurotropic and psychotropic (Dzhakhangirov et al., 1995, 1997; Benn and Jacyno, 1984; Zhu et al., 1996; Heubach and Schule, 1998; Wang and Xie, 1999). Early studies have shown that these alkaloids act as neurotoxins and can be subdivided into two main groups (Benn and Jacyno, 1984). Group one is comprised of alkaloids—neurotoxins act- ing at voltage-gated Na + channel. It is very intriguing that in spite of having very similar molecular skeletons, these alka- loids exhibit principally different (in some cases antagonist) ∗ Corresponding author. Tel.: +998 71 1627897; fax: +998 71 1206475. E-mail address: bakhrasu@yahoo.com (B.F. Rasulev). actions varying from poisonous (Fig. 1, aconitine) to therapeu- tic (Fig. 1, lappaconitine). Thus, aconitine-like compounds are strong arrhytmogens and have been reported to possess three principally important functional residues along with positively charged nitrogen atom responsible for the voltage-gated Na + channel opening activity. In contrast, lappaconitine is applied as antiarrhythmic agent due to inducing sodium channel block- ade. Group two is represented by compounds with curarelike (curariform) activity—neuronal nicotinic acetylcholine receptor (nAChR) binders (Fig. 1, methyllycaconitine). The recent advances in combinatorial chemistry methods have allowed a thousand of compounds to be synthesised and screened in parallel in vitro assays. Consequently “drug- likeness” concept (Muegge, 2003; Lipinski et al., 1997; Lipinski, 2000) has become even more important issue and the need in simple techniques for the lead identification has also arisen. It is commonly believed that drug-like molecules tend to possess cer- tain properties (Muegge, 2003). A number of filters (i.e. rules) for selecting drug-like compounds have been proposed starting from pioneering Lipinski’s “rule of five” to more sophisticated 1382-6689/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.etap.2007.10.035