Identification and validation of fusidic acid and flufenamic acid as inhibitors of SARS-CoV-2 replication using DrugSolver CavitomiX.

In this work, we present DrugSolver CavitomiX, a novel computational pipeline for drug repurposing and identifying ligands and inhibitors of target enzymes. The pipeline is based on cavity point clouds representing physico-chemical properties of the cavity induced solely by the protein. To test the pipeline's ability to identify inhibitors, we chose enzymes essential for SARS-CoV-2 replication as a test system. The active-site cavities of the viral enzymes main protease (Mpro) and papain-like protease (Plpro), as well as of the human transmembrane serine protease 2 (TMPRSS2), were selected as target cavities. Using active-site point-cloud comparisons, it was possible to identify two compounds-flufenamic acid and fusidic acid-which show strong inhibition of viral replication. The complexes from which fusidic acid and flufenamic acid were derived would not have been identified using classical sequence- and structure-based methods as they show very little structural (TM-score: 0.1 and 0.09, respectively) and very low sequence (~ 5%) identity to Mpro and TMPRSS2, respectively. Furthermore, a cavity-based off-target screening was performed using acetylcholinesterase (AChE) as an example. Using cavity comparisons, the human carboxylesterase was successfully identified, which is a described off-target for AChE inhibitors.

Matrix algorithms for solving (in)homogeneous bound state equations.

In the functional approach to quantum chromodynamics, the properties of hadronic bound states are accessible via covariant integral equations, e.g. the Bethe-Salpeter equation for mesons. In particular, one has to deal with linear, homogeneous integral equations which, in sophisticated model setups, use numerical representations of the solutions of other integral equations as part of their input. Analogously, inhomogeneous equations can be constructed to obtain off-shell information in addition to bound-state masses and other properties obtained from the covariant analogue to a wave function of the bound state. These can be solved very efficiently using well-known matrix algorithms for eigenvalues (in the homogeneous case) and the solution of linear systems (in the inhomogeneous case). We demonstrate this by solving the homogeneous and inhomogeneous Bethe-Salpeter equations and find, e.g. that for the calculation of the mass spectrum it is as efficient or even advantageous to use the inhomogeneous equation as compared to the homogeneous. This is valuable insight, in particular for the study of baryons in a three-quark setup and more involved systems.

Nucleon mass from a covariant three-quark Faddeev equation.

We report the first study of the nucleon where the full Poincaré-covariant structure of the three-quark amplitude is implemented in the Faddeev equation. We employ an interaction kernel which is consistent with contemporary studies of meson properties and aspects of chiral symmetry and its dynamical breaking, thus yielding a comprehensive approach to hadron physics. The resulting current-mass evolution of the nucleon mass compares well with lattice data and deviates only by ∼5% from the quark-diquark result obtained in previous studies.

Aspects of the confinement mechanism in Coulomb-gauge QCD.

Phenomenological consequences of the infrared singular, instantaneous part of the gluon propagator in the Coulomb gauge are investigated. The corresponding quark Dyson-Schwinger equation is solved, neglecting retardation and transverse gluons and regulating the resulting infrared singularities. While the quark propagator vanishes as the infrared regulator goes to zero, the frequency integral over the quark propagator stays finite and well defined. Solutions of the homogeneous Bethe-Salpeter equation for the pseudoscalar and vector mesons as well as for scalar and axial-vector diquarks are obtained. In the limit of a vanishing infrared regulator the diquark masses diverge, while meson properties and diquark radii remain finite and well defined. These features are interpreted with respect to the resulting aspects of confinement for colored quark-quark correlations.