title: Insights from Fragment Hit Binding Assays by Molecular Simulations.
abstract: Novel bioactive molecules can be rationally designed by growing and linking small fragments. Because fragments are fast and promiscuous, it is common to have contradictory hit results between different experimental screening techniques. Here, we simultaneously determine fragment binding poses, affinities, and kinetics on a focused library of 42 fragments against the serine protease factor Xa using multimillisecond molecular dynamics simulations. We predict experimental poses of 12 over 15 S1 crystal structures, and affinities are recovered for 4 out of 6. A kinetic map of protein cavities is computed in terms of on- and off-rates as well as insights into secondary ligand poses. The results suggest that the approach can be useful to recapitulate discordant fragment screening data.
authors.affiliation: Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB) , Doctor Aiguader 88, 08003 Barcelona, Barcelona, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Ferruz
authors.affiliation: Acellera, Barcelona Biomedical Research Park (PRBB), Doctor Aiguader 88, 08003, Barcelona, Barcelona, Spain.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Harvey
authors.affiliation: Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra , Doctor Aiguader 88, 08003 Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Mestres
authors.affiliation: Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB) , Doctor Aiguader 88, 08003 Barcelona, Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats , Passeig Lluis Companys 23, 08010 Barcelona, Barcelona, Spain.
authors.forename: Gianni
authors.initials: G
authors.lastname: De Fabritiis
mesh_terms: D001681:Biological Assay; D020134:Catalytic Domain; D015951:Factor Xa / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D010446:Peptide Fragments; D054852:Small Molecule Libraries; D015951:Factor Xa