In silico investigation of the mechanism of ricin-catalysed depurination reaction and design of novel ricin inhibitors
Ricin is a dimeric enzyme found in the castor bean plant. It is extremely toxic with a fatal dose for humans ranging from 0.1-1.0 ug/kg. This has lead to its use as a biological weapon. Cell death is caused when ricin ceases the protein synthesis by removing a specific adenine (A-4324) of the GAGA tetra loop of 28S ribosomal RNA. Despite this destructive feature, ricin has been touted as a potential therapeutic agent where applications such as immunotoxins to treat cancer, AIDS and other diseases are actively being pursued. However, the prime challenge in such applications is the non specific cytotoxicity of ricin, which cannot currently be treated due to the absence of an effective antidote. The primary objective of this thesis is to describe the catalytic mechanism of ricin using computational reaction dynamics. For an accurate simulation of the ricin-catalysed reaction, a reasonable model of the target natural substrate is required.
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