ABSTRACT
The major cysteine protease of Trypanosoma cruzi, cruzain (CRZ), has been described as a therapeutic target for Chagas' disease, which affects millions of people worldwide. Thus, a series of CRZ inhibitors has been studied, including a new competitive inhibitor, Nequimed176 (NEQ176). Nevertheless, the structural and dynamic basis for CRZ inhibition remains unclear. Hoping to contribute to this ever-growing understanding of timescale dynamics in the CRZ inhibition mechanism, we have performed the first study using 100 ns of molecular dynamics (MD) simulations of two CRZ systems in an aqueous solvent under pH 5.5: CRZ in the apo form (ligand free) and CRZ complexed to NEQ176. According to the MD simulations, the enzyme adopts an open conformation in the apo form and a closed conformation in the NEQ176-CRZ complex. We also suggest that this closed conformation is related to the hydrogen-bonding interactions between NEQ176 and CRZ, which occurs through key residues, mainly Gly66, Met68, Asn69, and Leu160. In addition, the cross-correlation analysis shows evidence of the correlated motions among Ala110-Asp140, Leu160-Gly189, and Glu190-Gly215 subdomains, as well as, the movements related to Ala1-Thr59 and Asp60-Pro90 regions seem to be crucial for CRZ activity.
Subject(s)
Cysteine Endopeptidases/chemistry , Cysteine Proteinase Inhibitors/chemistry , Molecular Dynamics Simulation , Protozoan Proteins/chemistry , Solvents/chemistry , Trypanosoma cruzi/enzymology , Binding Sites , Catalytic Domain , Cysteine Proteinase Inhibitors/pharmacology , Hydrogen Bonding , Hydrogen-Ion Concentration , Models, Molecular , Molecular Conformation , Protein Interaction Domains and Motifs , Protozoan Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Flaviviridae/enzymology , Peptides/chemistry , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/chemistry , Viral Proteins/chemistry , Animals , Flaviviridae Infections/drug therapy , Humans , Molecular Structure , Viral Proteins/antagonists & inhibitorsABSTRACT
Hepatitis C, Dengue and West Nile virus are some of the most important flaviviruses, that share one important serine protease enzyme. Serine proteases are the most studied class of proteolytic enzyme and, in these cases, a primary target for drug discovery. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N- t-Boc amino acid esters derived of isomannide as potential serine proteases inhibitors.
Subject(s)
Amino Acids/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Enzyme Inhibitors/pharmacology , Mannitol/chemistry , Serine Endopeptidases/chemistry , Carbon/chemistry , Dengue Virus/metabolism , Flavivirus/metabolism , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Mannose/chemistry , Models, Chemical , Models, Molecular , Peptides/chemistry , Protein Conformation , Temperature , Viral Nonstructural Proteins/chemistryABSTRACT
Helicobacter pylori infection is the major causative factor of a number of gastric pathologies. Several classes of compounds have been identified as anti-H. pylori agents. Here we provide a review of anti-H. pylori compounds that have recently appeared in the literature, including the guanidino, antibiotics, acetamide, pyrazole and benzimidazole compounds.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Ulcer Agents/pharmacology , Helicobacter pylori/drug effects , Helicobacter Infections/drug therapy , Helicobacter Infections/microbiology , Humans , Stomach Ulcer/drug therapy , Stomach Ulcer/microbiologyABSTRACT
A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.
