title: Computer-aided drug design of falcipain inhibitors: virtual screening, structure-activity relationships, hydration site thermodynamics, and reactivity analysis.
abstract: Falcipains (FPs) are hemoglobinases of Plasmodium falciparum that are validated targets for the development of antimalarial chemotherapy. A combined ligand- and structure-based virtual screening of commercial databases was performed to identify structural analogs of virtual screening hits previously discovered in our laboratory. A total of 28 low micromolar inhibitors of FP-2 and FP-3 were identified and the structure-activity relationship (SAR) in each series was elaborated. The SAR of the compounds was unusually steep in some cases and could not be explained by a traditional analysis of the ligand-protein interactions (van der Waals, electrostatics, and hydrogen bonds). To gain further insights, a statistical thermodynamic analysis of explicit solvent in the ligand binding domains of FP-2 and FP-3 was carried out to understand the roles played by water molecules in binding of these inhibitors. Indeed, the energetics associated with the displacement of water molecules upon ligand binding explained some of the complex trends in the SAR. Furthermore, low potency of a subset of FP-2 inhibitors that could not be understood by the water energetics was explained in the context of poor chemical reactivity of the reactive centers of these compounds. The present study highlights the importance of considering energetic contributors to binding beyond traditional ligand-protein interactions.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Falgun
authors.initials: F
authors.lastname: Shah
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Jennifer
authors.initials: J
authors.lastname: Legac
authors.forename: Devleena
authors.initials: D
authors.lastname: Shivakumar
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
mesh_terms: D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology; D014584:User-Computer Interface; D014867:Water / Q000737:chemistry*
chemical_list: D011480:Protease Inhibitors; D011799:Quinazolines; D054852:Small Molecule Libraries; D013777:Tetrazoles; D014230:Triazoles; D014867:Water; C045574:1H-tetrazole; D003546:Cysteine Endopeptidases; C099607:falcipain