54 research outputs found
Insights into the Complex Formed by Matrix Metalloproteinase-2 and Alloxan Inhibitors: Molecular Dynamics Simulations and Free Energy Calculations
Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A) in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S1′ specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S1′ subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC50 = 7.06) is found for BAM, a compound exhibiting also selectivity (>20) towards MMP-2, as compared to MMP-9, the other member of the gelatinases
Design of multiple-target anticancer agents: a daunting challenge for the medicinal chemist
Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds
Many naturally occurring substances, traditionally used in popular medicines around
the world, contain the coumarin moiety. Coumarin represents a privileged scaffold for medicinal
chemists, because of its peculiar physicochemical features, and the versatile and easy synthetic
transformation into a large variety of functionalized coumarins. As a consequence, a huge number of
coumarin derivatives have been designed, synthesized, and tested to address many pharmacological
targets in a selective way, e.g., selective enzyme inhibitors, and more recently, a number of selected
targets (multitarget ligands) involved in multifactorial diseases, such as Alzheimer’s and Parkinson’s
diseases. In this review an overview of the most recent synthetic pathways leading to mono- and
polyfunctionalized coumarins will be presented, along with the main biological pathways of their
biosynthesis and metabolic transformations. The many existing and recent reviews in the field
prompted us to make some drastic selections, and therefore, the review is focused on monoamine
oxidase, cholinesterase, and aromatase inhibitors, and on multitarget coumarins acting on selected
targets of neurodegenerative diseases
Heterodimeric dual binding site cholinesterase inhibitors: surfing on the sub-nanomolar affinity
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