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In silico Investigations of membrane transporters activity of indole derivatives as SRC tyrosine kinase inhibitors

Membrane transporters (MTs) mediate many biological effects of xenobiotics and play an important role in pharmacokinetics and resistance of small molecule drugs. MTs from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate cellular uptake, efflux, and homeostasis of many essential nutrients and significantly influence drug pharmacokinetics. Although the influence of different MTs is variable in current pharmaceutical drug discovery, in diseases where drug combinations are very common, such as cancer and viral infections, predictive models for transporter substrates are particularly useful in highlighting the potential risks of drug-drug interactions (DDI). In addition to regulatory agencies issuing guidelines related to transporters drug-drug associated interactions (DDIs), the selection of viable drug candidates among biologically active compounds requires the evaluation of their transporter interaction profiles. [1] The aim of this study was to evaluate the membrane transporter activity of selected 2-oxindole derivatives (n=44) previously tested for SRC kinase activity [2] and sunitnib and PP1 as reference molecules. For this purpose, the ADMET Predictor® Transporters Module (Simulations Plus Inc., USA) was used, which includes a set of models for P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, and BSEP and provides substrate/non-substrate and inhibitor/non-inhibitor classification models as well as Km regression models. [3] Transporter interaction assessment results showed that the investigated 1-(3-benzylidene-2-oxoindolin-5-yl)-3-ethylureas (21-28), benzyl-3-(3-benzylidene-2-oxoindolin-5-yl)urea (29-35) and benzyl-3-(3-benzylidene-2-oxoindolin-5-yl)thiourea derivatives (36-44) were P-glycoprotein substrates (Pgp_Substr), including the reference compounds sunitinib and PGP1. In contrast 3-benzylidene-5-(4-fluorophenyl)indolin-2-one (1-8), 5-(4-fluorophenyl)-3-(phenylimino)indolin-2-one (9-12), benzyl-5-(4-fluorophenyl)-3-(phenylimino)indolin-2-one (13-16) and benzyl-5-(4-fluorobenzylamino)-3-(phenylimino)indolin-2-ones (17-20) were P-glycoprotein non-substrates. The majority of the 2-oxindoles studied showed Pgp inhibitory activity, with the exception of compounds bearing p-COOH in almost all types studied compounds (8, 28, 36, and 44), as well as p-Cl (21), p-F and o-, p-di-F (22 and 25, respectively), p-N(CH3)2 (26) and p-O-CH3 (27) in the benzylidene moiety of ethylurea-2-oxindoles, among which the most active SRC kinase inhibitor was revealed and this whole group was also found to have the lowest ADMET risks among all the studied compounds. Among the studied transporter interactions, the substrate activity was also revealed with BCRP while almost all the studied compounds also showed the inhibitory activity against BCRP, BSEP, OAT1, OAT3, and OCT1 transporters. [1] A. Schlessinger, M. A. Welch, H. van Vlijmen, K. Korzekwa, P. W. Swaan, P. Matsson5, Clin. Pharmacol.Ther. 2018, 104, 818. [2] Z. Kilic-Kurt, F. Bakar, S. Olgen, Arch. Pharm. Chem. Life Sci. 2015, 348, 1. [3] ADMET Predictor® (2021) Simulations Plus, Inc., USA, www.simulations-plus.com.

2-Oxindoles ; Tyrosine kinase inhibitors ; ADMET ; Membrane transporters interactions ; In silico study

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