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ADMET Properties and Correlation Studies in a Series of Stimulants of the WADA List of Prohibited Substances

Structural features of stimulants (World Anti-Doping Agency List of prohibited substances, WADA 2016) and the impact of different substituents on their physico-chemical, pharmacological and toxicological properties were analyzed in correlation studies using molecular descriptors (MlogP, Mr, TPSA and V), topological indices (F, X, J, H, W, WW, Wp and Sz), drug-likeness scores (dls) computed for GPCR ligand (GPCR l-dls), ion channel modulator (ICM-dls), kinase inhibitor (KI-dls), nuclear receptor ligand (NRL-dls), protease inhibitor (PI-dls) and enzyme inhibitor (EI-dls), as well as ADMET parameters including predicted toxicological properties. Molecular descriptors were calculated using Molinspiration property engine v2014.11 and Molinspiration bioactivity score v2014.03 (www.molinspiration.com) while topological indices were computed by means of Chem Axon software (www.chemicalize.org). The ADMET properties were predicted by MedChem StudioTM 4.0 and ADMET PredictorTM 8.0 (Simulations Plus, Inc., USA). All analysis were performed using OriginPro 8.0 software (Origin Laboratories, USA). Insignificant drug-likeness scores were computed for most investigated molecules, except for ICM-dls (fenbutrazate, N-methylephedrine, methylphenidate, oxilofrine, sibutramine and strichnine, 0, 21–0, 53), KI-dls and PI-dls for strichnine (0, 56 and 0, 21, respectively), and EI-dls (pemoline, 0.26). The results of QSAR studies revealed the following significant correlations: Mr vs. Platt index (r = 0.9536, y = 0, 2381x - 9.104) and Mr vs. V (r = 0.9498, y = 0, 9022x +2165). According to ADMET Predictor analysis, these molecules are mostly either CYP substrates and/or CYP inhibitors. For investigated compounds the following toxicological parameters were also predicted: ADMET risk between 0.0 - 4.446, CYP risk 0.0 – 1.956 and TOX risk 0.0 - 3.446.

ADMET ; drug-likeness ; molecular descriptors ; QSAR ; stimulants

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