14 January 2019

(Not) getting misled by crystal structures: part 5 – conformational heterogeneity

It’s been a while since the last installment in our “getting misled” series. One of the key issues with crystallography is that ligands are almost always modeled as binding in a single conformation. This does not necessarily reflect reality, as we discussed here. Indeed, as described here and here, subtle changes can cause ligands to dramatically change their binding modes, which could reflect the fact that the initial ligand itself had multiple binding modes, and the change simply shifts the equilibrium. In an effort to proactively seek out disparate binding conformations, Henry van den Bedem and a group of collaborators from Stanford, UCSF, Schr√∂dinger, and Universit√© Paris-Saclay have created a new program, which they describe in J. Med. Chem. (See here for In The Pipeline’s discussion.)

The open-source program, called qFit-ligand, starts with an existing protein-ligand structure and an electron density map. It first breaks the ligand into rigid fragments (such as rings) and rotatable bonds. Each rigid group is then allowed to move around and rotate to fit the density. Of course, this might entail the rest of the molecule moving as well to avoid bumping into the protein; up to five positions are stored for each rigid group. Combinations that best match the electron density are retained: for a ligand with three rigid groups, 15 conformations would be considered. Importantly, the entire process is automated.

The researchers validated qFit-ligand against a set of 73 reasonably high-resolution structures from the protein data bank (PDB) that had included two different binding conformations; they started with just one of the reported conformations and used their program to find the second. qFit-ligand was very effective at identifying cases where a terminal portion of the molecule had flipped or rotated, though less so for more difficult cases such as displacement of the entire ligand.

Next, the researchers turned to the D3R dataset of 145 high-quality, manually curated crystal structures, where qFit-ligand correctly identified 7 of the 10 structures with alternate conformations, and even identified an alternative conformation for a ligand that had not previously been detected.

The researchers then examined a large set of crystal structures that had been flagged as potentially dubious, and found several could be improved by including alternate conformations. Similarly, an examination of all 126 crystal structures of BRD2-4 bromodomain-ligand complexes in the PDB revealed that 12 almost certainly had previously undetected alternate binding conformations; another 24 likely did.

qFit-ligand strikes me as a powerful tool for getting beyond the static picture usually presented by crystallography. Because the program is automated, the researchers note, it should be complementary to high-throughput approaches such as PanDDa (which we described here). Of course, using qFit-ligand effectively assumes that everyone is aware of the potential for both false positives and negatives. As the researchers conclude, “communication between structural biologists, computational chemists, and medicinal chemists remains a requisite for successful, rational design.”

07 January 2019

Fragment events in 2019

Happy New Year! Lots of exciting events scheduled this year, many of them in the first half.

March 20-22: Although not exclusively fragment-focused, the Sixth NovAliX Conference on Biophysics in Drug Discovery will have lots of relevant talks, and will be held in the nice city of Nice Cannes. You can read my impressions of the 2018 event here, the 2017 Strasbourg event here, and Teddy's impressions of the 2013 event herehere, and here.

March 24-26: The Royal Society of Chemistry's Fragments 2019 will be held in the original Cambridge. This is the seventh in an esteemed conference series that alternates years with the FBLD meetings. You can read my impressions of Fragments 2013 and Fragments 2009.

April 9-10CHI’s Fourteenth Annual Fragment-Based Drug Discovery, the longest-running fragment event, will be held in San Diego. You can read impressions of the 2018 meeting here, the 2017 meeting here, the 2016 meeting here; the 2015 meeting herehere, and here; the 2014 meeting here and here; the 2013 meeting here and here; the 2012 meeting here; the 2011 meeting here; and 2010 here. Also, Ben Davis and I will teach an FBDD short course on April 8, and it comes with dinner!

April 28-May 1: If you're looking for an even more intensive course, the 15th EFMC Short Course on Medicinal Chemistry is entitled "Small Becomes Big in Medicinal Chemistry: Fragment-based Drug Discovery." This will be held near Leiden, and as the number of participants is limited to 35, you should register early.

May 19-21: Structures are often critical for FBLD. The Second Annual Industrial Biostructures America Conference, which will be held in La Jolla, CA, is sponsored by Proteros and will cover a range of structural techniques.

September 1-4: BrazMedChem2019 will be held in the Brazilian city of Pirinopolis, and I know there will be some FBLD-relevant content.

November 12-15: The third FBDD Down Under will take place in Melbourne, and given the success of the first, it should be excellent.

Fourth Quarter: If you can't make it to Nice, NovAliX will also be holding a biophysics meeting for the first time in Japan, likely Osaka or Tokyo, sometime between mid-October and early December. Stay tuned for further details.

Know of anything else? Add it to the comments or let us know!