Speaker Abstract RCMM 2017: Associate Professor Dr. Mohd Firdaus Mohd Raih

Computational 3D protein side-chain comparisons: Applications in drug repurposing and toxicity screening

Mohd Firdaus Raih

School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi.

The Protein Data Bank (3D) is the central repository for publicly available data of macromolecular 3D structures. Among the entries are structures in complex with drugs thus making it possible for the 3D arrangements of amino acid side chains that are involved in specific interactions with the drugs to be known. Searching for these known arrangements in other PDB structures enable other analogous 3D arrangements in proteins that are not evolutionarily related to be identified. These proteins have the potential to proceed as targets for drug repurposing/repositioning. The concept of drug repositioning itself is not new. However, no attempt has systematically been carried out on the scale of the whole PDB. This scale of screening has not been attempted before because previous work has focused only on specific drugs. Our group has developed 3D motif searching algorithms that are able to search for similarities of side chain arrangements using vector graphical representations generated from the Cartesian coordinate data of the PDB records. Previous work has shown that our approach is unique and has clear advantages over other methods. We deployed our algorithms to carry out a whole PDB search for analogs to known drug binding sites. The capability to systematically and periodically execute such searches will allow for a sentinel system to identify potential candidates for drug repositioning as and when they become available. The same principle can be applied to identify unintended targets that may cause drug toxicity. In turn, the use of such computational upstream approaches can lead to significant cost saving and reduced capital investment required for drug development, even in the event that only a small number of proteins can be identified as an alternative target for an existing drug or explain the toxicity of a known drug.