In silico screening Background: The most common method for finding hits involves searching through libraries of molecules using high‐throughput screening to reveal compounds with promising activity. Instructions: Read the passage below on screening molecules through computer modeling. Learning Goals: To understand the advantages and limitations of screening molecules through computer simulations. The rise in computing power, especially in the area of protein modeling, allows library compounds to be “flown” into a binding pocket that is modeled on a computer. Binding energies can then be estimated to approximate the Ki of each library member. The process of matching a compound to a binding site is called docking. Estimating the binding energy is called scoring. The overall process of testing for biological activity using a computer simulation is called in silico screening or virtual screening. A very attractive aspect of in silico screening is that the library does not to be real. As long as one can draw the molecules in a computer, the computer will handle docking the molecule to the target protein. The logistics of obtaining, maintaining, and dispensing compounds for testing are unnecessary. The library can potentially be far larger than the one or two million compound libraries held by major pharmaceutical companies. While there are many attractive aspects to in silico screening, the method is still developing. One problematic aspect is scoring. Current scoring methods are somewhat inaccurate, and many compounds that are not strong binders are predicted to be hits. The number of false hits, or false positives, can be reduced by using multiple different scoring methods. Only compounds that are predicted to be active through multiple methods are selected as hits. This approach is called consensus scoring. The activity of any virtual hits must be confirmed by synthesizing a sample of the molecule and testing the compound in an in vitro screen. OPTIONAL‐Please participate in the online discussion forum.
10.2 Fragment Based Screening Fragment‐based screening video Please watch the online video (7 minutes, 58 seconds). A condensed summary of this video can be found in the Video summary page. OPTIONAL‐Please participate in the online discussion forum.