SwissParam 2023: A Modern Web-Based Tool for Efficient Small Molecule Parametrization

Most steps of drug
discovery are now routinely supported and accelerated
by computer-aided drug design tools. Among them, structure-based approaches
use the three-dimensional structure of the targeted biomacromolecule
as a major source of information. When it comes to calculating the
interactions of small molecules with proteins using the equations
of molecular mechanics, topologies, atom typing, and force field parameters
are required. However, generating parameters for small molecules remains
challenging due to the large number of existing chemical groups. The
SwissParam web tool was first released in 2011 with the aim of generating
parameters and topologies for small molecules based on the Merck molecular
force field (MMFF) while being compatible with the CHARMM22/27 force
field. Here, we present an updated version of SwissParam, providing
various new features, including the possibility to setup covalent
ligands. Molecules can now be imported from different file formats
or via a molecular sketcher. The MMFF-based approach has been updated
to provide parameters and topologies compatible with the CHARMM36
force field. An option was added to generate small molecule parametrizations
following the CHARMM General Force Field via the multipurpose atom-typer
for CHARMM (MATCH) approach. Additionally, SwissParam now generates
information on probable alternative tautomers and protonation states
of the query molecule so that the user can consider all microspecies
relevant to its compound. The new version of SwissParam is freely
available at www.swissparam.ch and can also be accessed through a newly implemented command-line
interface.