Democratizing computational FBLD with BMaps
Computational approaches to FBLD continue
to gain in power. For the most part, they require significant knowledge and installation
of expensive, customized software. To remedy this, John Kulp, III and colleagues
at Conifer Point Pharmaceuticals have introduced a new web-based application,
BMaps, which they describe in a recent J. Chem. Inf. Mod. paper.
As the researchers note (and
appropriately reference), there are more than a dozen virtual fragment-based
design tools and another dozen web-based tools. BMaps (for Boltzmann Maps) aims
to provide a full range of functions, from visualizing proteins, finding hot spots,
docking fragments, and growing them. It also provides information on the energetics
of bound water molecules, which as we’ve written can be crucial players in
optimizing protein-ligand interactions.
Two key techniques used by BMaps
are Grand Canonical Monte Carlo (GCMC) simulations and Simulated Annealing of
Chemical Potential (SACP). The first entails comprehensive sampling of different
fragment conformations on a protein of interest and assessing binding free
energy. The second tool “forcefully inserts fragments into all the binding
sites of the protein” and then removes them slowly to evaluate which are most
difficult to remove, and thus most tightly bound. Together, GCMC-SACP can be
used to evaluate fragment binding to any protein uploaded to the site from the
protein data bank, AlphaFold, or any other source.
One nice feature of BMaps is a repository
of several hundred proteins each with more than 100 fragment and water
simulations. BMaps also contains a database of more than 4000 fragments,
including MiniFrags. Users can import their own fragments or computationally deconstruct
larger ligands. The paper itself is quite short, but the supporting information
provides more guidance on how to use the software.
The researchers “aim to democratize
the availability of accurate fragment and water maps,” a laudable goal. Most computational
features are available with a free account, though with restrictions on the
number of operations per month.
BMaps looks quite powerful and
easy to use, but I do wish the researchers had included some full case studies,
for example those used by the free FastGrow tool we highlighted last year. Try
it out and let the community know what you think!