changing poses in drug-target binding

directory of Chem Help ASAP videos: https://www.chemhelpasap.com/youtube/ On the screen is an early hit from a drug campaign that was striving to inhibit part of something called the complement system, which is part of the immune response pathway. The specific target in the complement system is Factor B. The hit had promising potency on Factor B with an IC50 of 6.6 micromolar. Not only could the researchers measure the IC50 value, but they also managed to get a cocrystal of the hit bound to Factor B. Here is the x-ray structure of the bound hit. This is entry 6QSW from the Protein Data Bank. The hit is in the middle of the pocket in grey. The researchers knew exactly how the hit was engaging with the target. With a confirmed and validated hit in hand, the researchers started making new analogues of the hit to see if they could improve the potency. Of course, the x-ray cocrystal helped guide the design of new analogues. Here is one of the changes they explored. They modified the naphthalene ring and replaced it with an indole. Specifically, they replaced this 6-membered ring with a 5-membered ring. This is an example of how chemists will make changes to a structure to gain an understanding of the SAR of a series of compounds. Naturally, the scientists assumed that the binding pose – the placement of the molecule in the target binding pocket – would be the same. When they obtained a cocrystal of the indole analogue, they were surprised. The x-ray data indicated that the position of the ring system had changed. So, image this axis in the indole structure. Rotation about this carbon-carbon bond exchanges the position of the indole ring and the bromine. The structure on the far right shows the changes more clearly. The indole has swung around to the left, and the bromine to the right. Changes in a binding pose are not uncommon, especially in relatively weak-binding compounds. Researchers in a lead optimization program must be vigilant to test their assumptions, including the assumption that the binding pose is consistent from one analogue to the next. The cocrystal of this indole hit has not been deposited in the PDB, but you can find images of the structure in the reference at the bottom of the screen. The researchers continued their optimization program and built on the binding information based on the indole analogue. On the screen we have the original hit, the indole hit, and the fully optimized compound with an IC50 on Factor B of 12 nanomolar. So that is close to a 1000-fold improvement in potency from the indole hit. At the time of this video, the compound has recently been approved for the treatment of paroxysmal nocturnal hemoglobinuria, which involves the unwanted destruction of red blood cells by the complement system. Inhibition of Factor B helps suppress the pathway and improve patient outcomes.