Computational Chemistry or in silico experiments have advantages- easier, safer, faster, cheaper, may reduce variability than biological experiments. Use computers to simulate, predict, and study the properties of molecules-help explain, explore new functions, predict behaviors and design new molecules.
Goal is to create new drugs for Neglected Tropical Diseases NTDs by using computational chemistry. Focus on two tropical diseases to perform target-based design of small molecules to act as drugs for the disease.
1) Sleeping sickness- 50,00 deaths/year target is pteridine reductase essential enzyme not found in the human genome,
2) Tuberculosis- multi-drg resitsance, treatment is lengthy and results in poor compliance. Target enzyme: Thymidylate synthase.
Methods:
Stepwise protocol to determine small molecules that can be used as drugs for NDTs.
1) Find an essential protein in the pathogen that isn't present in humans that have 3D structure for.
2) Download small molecule libraries and docking programs
3) dock small molecules to protein-find lowest binding energy, repeat.
4) Find common structures of top hits
5) Experiment with R groups on common structure to improve strength of bonds between molecule and protein structure
6) perform in vitro assays to examine binding energies between small molecules and protein.