title: Synthesis, biological evaluation, hydration site thermodynamics, and chemical reactivity analysis of α-keto substituted peptidomimetics for the inhibition of Plasmodium falciparum.
abstract: A new series of peptidomimetic pseudo-prolyl-homophenylalanylketones were designed, synthesized and evaluated for inhibition of the Plasmodium falciparum cysteine proteases falcipain-2 (FP-2) and falcipain-3 (FP-3). In addition, the parasite killing activity of these compounds in human blood-cultured P. falciparum was examined. Of twenty-two (22) compounds synthesized, one peptidomimetic comprising a homophenylalanine-based α-hydroxyketone linked Cbz-protected hydroxyproline (39) showed the most potency (IC50 80 nM against FP-2 and 60 nM against FP-3). In silico analysis of these peptidomimetic analogs offered important protein-ligand structural insights including the role, by WaterMap, of water molecules in the active sites of these protease isoforms. The pseudo-dipeptide 39 and related compounds may serve as a promising direction forward in the design of competitive inhibitors of falcipains for the effective treatment of malaria.
authors: School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States; School of Pharmacy, Department of Pharmaceutical Sciences, Loma Linda University, Loma Linda, CA 92350, United States.
authors: David J
authors: DJ
authors: Weldon
authors: School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States.
authors: Falgun
authors: F
authors: Shah
authors: School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States; National Center for Natural Products Research, University of Mississippi, University, MS 38677, United States.
authors: Amar G
authors: AG
authors: Chittiboyina
authors: School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States.
authors: Anjaneyulu
authors: A
authors: Sheri
authors: School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States.
authors: Raji Reddy
authors: RR
authors: Chada
authors: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143, United States.
authors: Jiri
authors: J
authors: Gut
authors: Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143, United States.
authors: Philip J
authors: PJ
authors: Rosenthal
authors: Schrodinger, Inc., 120 West 45th Street, 17th Floor, New York, NY 10036, United States.
authors: Develeena
authors: D
authors: Shivakumar
authors: Schrodinger, Inc., 120 West 45th Street, 17th Floor, New York, NY 10036, United States.
authors: Woody
authors: W
authors: Sherman
authors: School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States.
authors: Prashant
authors: P
authors: Desai
authors: School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States.
authors: Jae-Chul
authors: JC
authors: Jung
authors: School of Pharmacy, Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, United States; National Center for Natural Products Research, University of Mississippi, University, MS 38677, United States. Electronic address: mavery@olemiss.edu.
authors: Mitchell A
authors: MA
authors: Avery
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D006860:Hydrogen Bonding; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry*; D057786:Peptidomimetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D007659:Ketones; D010455:Peptides; D057786:Peptidomimetics; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3
keywords: Cruzain; Drug resistance; Falcipain; Malaria; Peptidomimetic