International Journal of Biological Macromolecules 48 (2011) 292–300 Contents lists available at ScienceDirect International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac Identification of novel selective antagonists for cyclin C by homology modeling and virtual screening P. Sarita Rajender, M. Vasavi, Uma Vuruputuri ∗ Department of Chemistry, Nizam College, Basheerbagh, Hyderabad 500001, Andhra Pradesh, India article info Article history: Received 14 August 2010 Received in revised form 27 November 2010 Accepted 29 November 2010 Available online 5 December 2010 Keywords: Cyclin-dependent kinase Cyclin C Homology modeling Virtual screening ADME abstract Cancer is a global multidrug resistant calamity, demanding an urgent need to design a novel/potent anti cancer agent. CDK8, 3/cyclin C biosynthetic pathway plays a specific role in G 0 /G 1 /S phases of cell cycle. Cyclin C is identified as a potential anti cancer target candidate. In order to understand the mechanism of ligand binding and interaction between ligand and cyclin C, a 3D homology model for cyclin C is generated. The cyclin C binding groove can be checked by small ligand molecules leading to inhibition. Virtual screening of molecules from an online data base of ChemBank library throws light to arrive at possible inhibitors for cyclin C inhibition. The molecules with better docking scores and acceptable ADME properties were prioritised to obtain potential lead molecules as cyclin C inhibitors. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Cyclin-dependent kinase complexes (CDK/cyclin) play a key role in the regulation of cell cycle. Irregular activity of CDK complexes is frequently involved in cancer. Several CDK/cyclin inhibitors are in clinical trials. Targeting a single CDK/cyclin complex for cell cycle arrest in a particular phase could be a promising anti tumour strat- egy. Suppression of tumour growth by the arrest of cell proliferation in G 1 phase of cell cycle ceases the cell cycle progression, as the cells spend most of their time in G 0 /G 1 phase [1]. In the present study a new class of selective cyclin C inhibitors that causes cell cycle arrest in G 0 /G 1 phases are identified by using structure based drug design techniques [2]. Cyclin C is a highly conserved protein involved in the regulation of cell cycle from yeast to man. The physiological function of cyclin C is achieved by combining with its primary kinase partner CDK8. Cyclin C displays substrate specificity and regulates transcription by binding to CDK8 and CDK3 during cell cycle progression [3]. Cyclin C plays a novel role in the regulation of G 0 /G 1 /S and G 2 M phases of cell cycle [4]. Transcription in eukaryotes is complex, highly regulated, involv- ing several steps and requires the presence of multiple protein factors [5]. In higher eukaryotes, cyclin C associates with CDK8 and ∗ Corresponding author. E-mail addresses: vuma@osmania.ac.in, vuma1957@gmail.com (U. Vuruputuri). up-regulates transcription by phosphorylating carboxy-terminal domain (CTD) of RNA polymerase II [6]. CDK8/cyclin C is specif- ically involved in transcription by phosphorylating and targeting RNA Pol II CTD [7,8]. RNA Pol II is responsible for the synthesis of pre m-RNA complex in eukaryote cells shown in Fig. 1, steps 1–3. RNA initiates the formation of pre-initiation complex (PIC), in which Pol II and other transcriptional factors bind to the promoter DNA to help in the cell regulation. The yeast Srb 10, a cyclin- dependent kinase (CDK) regulated by Srb11cyclin, a homologue of mammalian CDK8/cyclin C complex, phosphorylates various transcriptional activators and activates transcription [9]. Transcrip- tional regulation is a Galactose mediated function under the control of Gal4 transcriptional activator [10]. In addition to cell cycle progression CDK8/cyclin C has a role in transcriptional repression and is a negative regulator of transcrip- tion represented in Fig. 1, steps 4 and 5.Transcriptional repression, an essential mechanism in the precise control of cell progres- sion is observed when CDK8/cyclin C complex phosphorylates CDK7/cyclin H, a subunit of general transcription initiation factor (TFIIH) in the region of its functionally unique amino and carboxy- terminal--helical domain. The phosphorylation represses both the ability of the TFIIH to activate transcription and CTD kinase activity which halts the formation of transcription initiation com- plex [11,12]. CDK8/cyclin C, apparent homologue of Srb 10/Srb11- phosphorylates CTD, prior to the association of RNA Pol II with transcription initiation complex, and prevents the entry of 0141-8130/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ijbiomac.2010.11.015