Inhibition of Porcine Aminopeptidase M (pAMP) by the Pentapeptide Microginins

Abstract

Aminopeptidase M (AMP) inhibition is of interest for several diseases, such as highly vascularized cancer types. AMP can be inhibited by linear pentapeptides isolated from Microcystis aeruginosa LTPNA08 (MG7XX). Porcine AMP inhibition—a model for human AMP—activity was spectrophotometrically measured by the formation of p-nitroanilide from L-leucine-p-nitroanilide substrate by AMP. AMP inhibition by MG770 exhibited comparable inhibition levels to amastatin (IC50 values: 1.20 ± 0.1 μM and 0.98 ± 0.1 μM, respectively), while MG756 was slightly less potent (with IC50 values of 3.26 ± 0.5 μM). Molecular modelling suggests a potential binding mode, based on the interaction with the Zn2+ cofactor, where MG770′s extra methyl group contributes to the disturbance of the Zn2+ cofactor complex and highlights the importance of hydrophobicity for the site.

Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design

“…The selected model of Tc Sir2 underwent molecular dynamics (MD) simulations, using a previously described protocol [ 32 ]. Tc Sir2 was simulated in the presence and absence of the cofactor NAD + to understand which amino acid residues contributed to the stability within the binding site ( Figure 2 ).…”

SARS-COV-2 Mpro conformational changes induced by covalently bound ligands

“…Prepared SARS-CoV-2 M pro structures were simulated as apostructures (without ligands) and covalently bound to ligands (N1 and N3). Molecular Dynamics (MD) simulations were carried out by using the Desmond engine (Bowers et al, 2006 , 2007 ) with the OPLS3e force-field (Harder et al, 2016 ) according to a previously described protocol (Ferreira et al, 2019 ). OPLS3e accomplishes this by incorporating a broad range of chemical moieties with greater and combining them on-the-fly to generate parameterization, followed by the assignment of partial charges (Roos et al, 2019 ).…”

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“…MGs contain from 3 to 6 residues and are characterized by the presence of N -terminal β-amino-α-hydroxy-decanoic acid (Ahda) or its variants [ 121 , 122 ]. They are also active against aminopeptidases [ 123 , 124 ], but showed no effects against proteases: trypsin, thrombin, plasmin, chymotrypsin, elastase and papain [ 125 ].…”