ORIGINAL PAPER Insights into mechanism of anticancer activity of pentacyclic oxindole alkaloids of Uncaria tomentosa by means of a computational reverse virtual screening and molecular docking approach Pawel Kozielewicz • Katarzyna Paradowska • Slavica Eric ´ • Iwona Wawer • Mire Zloh Received: 9 March 2014 / Accepted: 23 March 2014 / Published online: 24 May 2014 Ó Springer-Verlag Wien 2014 Abstract Alkaloid-rich extract from Uncaria tomentosa (cat’s claw) has been reported to cause apoptosis in cancer lines. Oxindole pentacyclic alkaloids of the plant are responsible for this effect, yet their biological mechanism of action is not fully understood. In this work the set of these alkaloids underwent an extensive theoretical study with reverse virtual screening and molecular docking methods implemented in AutoDock, AutoDock Vina, and Molegro Virtual Docker. The results from these computa- tional methods indicate that inhibition of several important targets including dihydrofolate reductase and mouse dou- ble minute 2 homolog (MDM2) may be responsible for the biological activity of the alkaloids. The docking results also show that the alkaloids can interact with Dvl-2, Akt-2, and leukotriene A4 hydrolase. Reverse virtual screening and molecular docking are valuable tools to aid identification of protein targets for bioactive hit molecules and could guide the design of in-depth biochemical activity tests and utilization of these alkaloids in anticancer drug development. Keywords Apoptosis Á Molecular docking Á Reverse virtual screening Á Oxindole alkaloids Á Uncaria tomentosa Introduction Uncaria tomentosa (cat’s claw) is a woody vine from the Peruvian Amazon. The bark, roots, and leaves of this plant have been used in traditional medicine by the native people of Peru since the Incas to treat a wide range of illnesses, such as diarrhea, rheumatic and gastrointestinal disorders, cancer, diabetes, and acne [1]. Traditionally, decoctions of U. tomentosa were prepared from roots and bark. The chemical profile of the plant constituents is diversified. The extracts of U. tomentosa bark contain quinovic acid gly- cosides, triterpenes, flavonoids (rutin and quercetin), phytosteroids (b-sitosterol, stigmasterol, and campesterol), and catechins. However, the most valuable chemicals are tetra- and pentacyclic oxindole and indole alkaloids. Two chemotypes of U. tomentosa have been established: one containing mainly pentacyclic, and the other containing tetracyclic indole and oxindole alkaloids in various parts of the plant [2]. Among the tetracyclic alkaloids, isorhynchophylline and rhynchophylline were proved to be N-methyl-D-aspartate (NMDA) receptor antagonists and Ca 2? channel blockers [3]. Furthermore, pentacyclic alkaloids have been reported to exhibit antiproliferative effects via stimulation of apoptosis [4–6]. In the past, we studied these compounds Electronic supplementary material The online version of this article (doi:10.1007/s00706-014-1212-y) contains supplementary material, which is available to authorized users. P. Kozielewicz (&) School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK e-mail: p.kozielewicz@pgr.bham.ac.uk K. Paradowska Á I. Wawer Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland S. Eric ´ University of Belgrade-Faculty of Pharmacy, Vojvode Stepe 450, 11000 Belgrade, Serbia M. Zloh Department of Pharmacy, University of Hertfordshire, Hatfield, Hertfordshire AL10 9AB, UK 123 Monatsh Chem (2014) 145:1201–1211 DOI 10.1007/s00706-014-1212-y