Computational simulation technique : computational studies and molecular modelling of proteins coordinated by metal-based chemotherapeutic agents

• Main Author: Sarsam, Susan W.
• Published: University of Reading 2011
• Subjects: 616.994061
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.553144

Research in the field of titanium-based complexes as potential anticancer drugs has led to impressive results in vitro, but there is still scope for further improvements. Significant effort has been put into synthetic research and biological evaluation of titanocene derivatives, as well as the identification of their main biological targets. Surprisingly, the area of computer-aided drug design (CADD) has not been utilized up-to-date for the design of novel titanium-based compounds. The work within the thesis describes the computational approaches employed to study the mode of action of titanium-based anticancer agents, highlighting the structural features required for biological activity. Consequently, novel titanium-based derivatives were designed and synthesized. Furthermore, the synthetic attempts for amidosilyl-substituted titanocene and ferrocene derivatives with potentially enhanced activity are also reported. The first chapter provides a thorough introduction into the developments in the field of metal-based antitumour agents with a particular emphasis on titanium-based agents and assessment of their cytotoxic activity. Chapter 2 describes the first systematic receptor- based docking approach utilized to understand the binding mode of titanium-based agents against human serum albumin (RSA). The first 3D-QSAR study, which is reported in Chapter 3, was performed on a series of titanocene complexes to gain insight into the key structural features vital for their biological activity and to advance the design of potent titanocene anticancer agents. The successful synthesis of six novel benzyl-substituted titanocene derivatives, which have been designed based on the 3D-QSAR analysis is described in Chapter 4. Chapter 5 focuses on the attempts made for the synthesis of a range of amidosilyl-substituted titanium and iron-based metallocenes. Although the amidosilyl- substituted derivatives could not be obtained as pure compounds, six titanium and iron- based metallocenes were successfully synthesized. Chapter 6 summarizes the results obtained and provides suggestions for areas of future research.