title: Genetic and structural study of DNA-directed RNA polymerase II ofTrypanosoma brucei, towards the designing of novel antiparasitic agents.
abstract: Trypanosoma brucei brucei(TBB) belongs to the unicellular parasitic protozoa organisms, specifically to theTrypanosomagenus of theTrypanosomatidaeclass. A variety of different vertebrate species can be infected by TBB, including humans and animals. Under particular conditions, the TBB can be hosted by wild and domestic animals; therefore, an important reservoir of infection always remains available to transmit through tsetse flies. Although the TBB parasite is one of the leading causes of death in the most underdeveloped countries, to date there is neither vaccination available nor any drug against TBB infection. The subunit RPB1 of the TBB DNA-directed RNA polymerase II (DdRpII) constitutes an ideal target for the design of novel inhibitors, since it is instrumental role is vital for the parasite's survival, proliferation, and transmission. A major goal of the described study is to provide insights for novel anti-TBB agents via a state-of-the-art drug discovery approach of the TBB DdRpII RPB1. In an attempt to understand the function and action mechanisms of this parasite enzyme related to its molecular structure, an in-depth evolutionary study has been conducted in parallel to thein silicomolecular designing of the 3D enzyme model, based on state-of-the-art comparative modelling and molecular dynamics techniques. Based on the evolutionary studies results nine new invariant, first-time reported, highly conserved regions have been identified within the DdRpII family enzymes. Consequently, those patches have been examined both at the sequence and structural level and have been evaluated in regard to their pharmacological targeting appropriateness. Finally, the pharmacophore elucidation study enabled us to virtuallyin silicoscreen hundreds of compounds and evaluate their interaction capabilities with the enzyme. It was found that a series of chlorine-rich set of compounds were the optimal inhibitors for the TBB DdRpII RPB1 enzyme. All-in-all, herein we present a series of new sites on the TBB DdRpII RPB1 of high pharmacological interest, alongside the construction of the 3D model of the enzyme and the suggestion of a newin silicopharmacophore model for fast screening of potential inhibiting agents.
authors.affiliation: Department of Informatics and Telecommunications, National and Kapodistrian University of Athens, Athens, Greece; Computational Biology & Medicine Group, Biomedical Research Foundation, Academy of Athens, Athens, Greece; Computer Engineering and Informatics Department, University of Patras, Patra, Greece.
authors.forename: Louis
authors.initials: L
authors.lastname: Papageorgiou
authors.affiliation: Computer Engineering and Informatics Department, University of Patras , Patra , Greece.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Megalooikonomou
authors.affiliation: Computational Biology & Medicine Group, Biomedical Research Foundation, Academy of Athens, Athens, Greece; Computer Engineering and Informatics Department, University of Patras, Patra, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Vlachakis
keywords: Computational biology; DNA-directed RNA polymerase II; Homology modelling; Molecular dynamics; Phylogenetic analysis; Structural models; Trypanosoma brucei brucei