Probing inhibition mechanisms of adenosine deaminase by using molecular dynamics simulations

Abstract

Adenosine deaminase (ADA) catalyzes the deamination of adenosine, which is important in purine metabolism. ADA is ubiquitous to almost all human tissues, and ADA abnormalities have been reported in various diseases, including rheumatoid arthritis. ADA can be divided into two conformations based on the inhibitor that it binds to: open and closed forms. Here, we chose three ligands, namely, FR117016 (FR0), FR221647 (FR2) (open form), and HDPR (PRH, closed form), to investigate the inhibition mechanism of ADA and its effect on ADA through molecular dynamics simulations. In open forms, Egap and electrostatic potential (ESP) indicated that electron transfer might occur more easily in FR0 than in FR2. Binding free energy and hydrogen bond occupation revealed that the ADA-FR0 complex had a more stable structure than ADA-FR2. The probability of residues Pro159 to Lys171 of ADA-FR0 and ADA-FR2 to form a helix moderately increased compared with that in nonligated ADA. In comparison with FR0 and FR2 PRH could maintain ADA in a closed form to inhibit the function of ADA. The α7 helix (residues Thr57 to Ala73) of ADA in the closed form was mostly unfastened because of the effect of PRH. The number of H bonds and the relative superiority of the binding free energy indicated that the binding strength of PRH to ADA was significantly lower than that of an open inhibitor, thereby supporting the comparison of the inhibitory activities of the three ligands. Alanine scanning results showed that His17, Gly184, Asp295, and Asp296 exerted the greatest effects on protein energy, suggesting that they played crucial roles in binding to inhibitors. This study served as a theoretical basis for the development of new ADA inhibitors.

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“…These results demonstrate that weak interactions between molecules, including H bonds and halogen bonds, can be predicted and explained by analyzing the magnitude and positions of the minima and maxima in an electrostatic potential (ESP) on the molecular vdW surface. 53 The formed ligand (drug in Table 2)receptor (6M0J) complexes reveal that pi-pi stacking, pi-alkyl and halogen bonds are able to increase the binding affinity and explain the differences in binding energies. Furthermore, to evaluate the stability of the formed proteinligand complexes, these structures were subjected to fully solvated atomistic molecular dynamics (MD) simulations using VMD54 54 and NAMD.…”

Computer-Aided Approaches to De Novo Design of drug candidates targeting the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2)

“…Molecular dynamics (MD) simulations were further used to assess structural stability of the 6M0J and 6, 7 and 8 complexes respectively. These structures were subjected to fully solvated atomistic MD simulations using VMD 54,55 and NAMD. 56 MD simulations were conducted at 310 K for 40 ns.…”

Random acceleration and steered molecular dynamics simulations reveal the (un)binding tunnels in adenosine deaminase and critical residues in tunnels

“…10 ADA inhibitors are classied into two types: transition-and ground-state inhibitors. 11,12 Transition-state inhibitors of ADA resemble a tetrahedral transition-state intermediate as a result of deamination. 11 Ground-state inhibitors of ADA are similar to adenosine.…”

“…11,12 Transition-state inhibitors of ADA resemble a tetrahedral transition-state intermediate as a result of deamination. 11 Ground-state inhibitors of ADA are similar to adenosine. Furthermore, these two types of inhibitors are met with a number of problems, such as toxicity, poor oral absorption, and rapid metabolism.…”