Sezen Vatansever
Koc University, Turkey
Title: Fight against crimean congo hemorrhagic fever virus: Drug design based on repositioning known molecules
Biography
Biography: Sezen Vatansever
Abstract
Background: Crimean Congo Hemorrhagic Fever (CCHF) is the most important tick-borne viral disease of humans causing increasing numbers of fatal outbreaks or sporadic cases across a huge geographic area. CCHF virus (CCHFV), the causative agent of the illness is classified as BSL 4 pathogen and considered as a potential bio-terrorism agent in the wider world. In contrast with severity of the virus, currently no FDA-approved specific antiviral therapy is available. Ribavirin is the only therapeutic agent used for the disease, although there is no evidence of its efficacy. Our research aims to discover new drugs against CCHFV in a drug repositioning manner by using rational drug design methods. In order to achieve our aim, we proceed as following steps: Molecular Docking; Molecular Dynamics; Combined Docking and Molecular Docking Simulations and In Vito & In Vivo Tests. Molecular Docking: Molecular docking includes target identification: Viral capsid protein is chosen as the target protein. It’s active site is determined by literature-based search; Ligand sets: Small libraries which include all the FDA-approved drugs and natural compounds are downloaded from ZINC database. Additionally, the investigational antivirals are searched from published articles and the Drug Bank. Their structures are obtained from ZINC; Docking programs: In a comparative manner MVD, GOLD and Autodock Vina are used and Structure-based discovery of candidates and docking: Some of the best-scored candidates can be shared similar structures. Structure similarity search is made for those candidates by using ZINC structure-based search tool. In addition to ligand sets, resulting molecules are also docked into the protein. Molecular Dynamics (MD): It involves simulation of the capsid protein: To understand the dynamic behavior of capsid at different time scales, simulation is performed using the NAMD program. Combined Docking and MD Simulations: Steered MD (SMD) simulations is used to reveal structural changes in protein-ligand complexes which are obtained from docking study at the atomic level; Parametrization of non-standard drug-like compounds: Parametrization of drug candidates is required for SMD. In Vitro & In Vivo Tests: Viral hemorrhagic fevers continue to threat the world and CCHF is endemic in Turkey. Development of effective drugs for prevention of CCHF is now a priority for public health. Our drug repositioning approach minimizes the cost and the duration of the drug development by using computer-aided analysis with the feasibility of intelligent drug design. We completed the first step of the study. Three different compound group showed significant binding affinity to the target protein. Now, we are working on the second and third steps. We will move to labratory and clinical experiments after third step. Our methodology is unique for being the only computational study directed on CCHF. It lets us to discover potent virus-specific drugs to fight against the CCHFV. Besides, this novel approach will enable to find out specific antivirals for the treatment of emerging infectious diseases all around the world. More importantly, this work can give a solution for universal problem in virus-infected patients which are the duration of treatment and the overall survival rate of the patients.