Comparison of the Human A_2A Adenosine Receptor Recognition by Adenosine and Inosine: New Insight from Supervised Molecular Dynamics Simulations

Abstract

Adenosine deaminase converts adenosine into inosine. In contrast to adenosine, relatively little attention has been paid to the physiological roles of inosine. Nevertheless, recent studies have demonstrated that inosine has neuroprotective, cardioprotective, immunomodulatory, and antidepressive effects. Inosine was recently shown to be a less potent agonist than adenosine at the A adenosine receptor. To better depict the differences in the mechanisms of receptor recognition between adenosine and inosine, we carried out supervised molecular dynamics (SuMD) simulations, and the results are analyzed herein.

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

“…During SuMD simulations, the extracellular adenosine was able to break the ionic interaction between H264 (EL3) and E169 (EL2), as proposed for the binding process of the orthosteric adenosine . The stabilization of the incoming adenosine was generally associated with a partial loss of interaction between the protein and the already‐bound adenosine molecule, mainly due to the loss of hydrogen bonds with N253 (6.55) side chain (Figure ).…”

“…During SuMD simulations, the extracellular adenosine was able to break the ionic interaction between H264 (EL3) and E169 (EL2), as proposed for the binding process of the orthosteric adenosine. [4] The stabilization of the incoming adenosine was generally associated with a partial loss of interaction between the protein and the already-bound adenosine molecule, mainly due to the loss of hydrogen bonds with N253 (6.55) side chain (Figure 3). From a structural point of view, the agonist molecules did not explore the allosteric site recently proposed by Sun B. et al [45] During the simulations, indeed, the extended M270 (7.35) side chain acted as "gate-keeper", burying the accessory pocket formed by Tyr9 (1.35), Ile66 (2.64), Leu267 (7.32), Tyr271 (7.36) and Ile274 (7.39) side chains.…”

Insights into adenosine A2A receptor activation through cooperative modulation of agonist and allosteric lipid interactions

“…These studies show that, upon the addition of a full agonist, A2aR activation follows outward movements of TM5 and TM6 (including rotation in the latter), an inward shift of the intracellular part of TM7, and a vertical translation of TM3 [42,[61][62][63][64]. Also, A2aR has received a lot of attention regarding ligand binding, lipid allosteric modulation and its activation process in MD simulations [44,[65][66][67][68][69][70][71][72][73][74][75][76][77][78] partly because it is a receptor that has been crystallized in three distinct conformational states: inactive (in the presence of an antagonist or inverse agonist) [29,63,[79][80][81][82][83][84][85][86][87][88][89][90][91], intermediate (in the presence of an agonist) [92][93][94][95], and active (in the presence of an agonist plus modified or native stimulatory G proteins) [24,25] (S1 Table).…”

An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

“…Medicinal chemists were thus able to deeply investigate shallow and/or buried grooves, particularly those transient, impossible to be detected through the only observation of NMR and X-ray crystal data 12 . In this review, we have provided an overview of successful MD techniques mainly adopted in the last decade, to deepen undruggable targets-related drug discovery issues, such as protein-ligand/protein-protein interaction stability [21][22][23][24] , binding kinetics [25][26][27][28][29] and interaction mode [30][31][32] . In particular, we have focused on the application of MD on two specific types of considerably important undruggable targets, allosteric sites and protein-protein interactions.…”

“…In the last years the advances in software and hardware performance allowed researchers to adopt Molecular Dynamics (MD) with great success 20 to address drug discovery issues such as protein-ligand interaction stability [21][22][23][24] , binding kinetics [25][26][27][28][29] and binding process [30][31][32] . The understanding of molecular motions is basically the main issue related to molecular recognition and represents the evolution of the old idea of "Lock-and-key model" where a frozen receptor can house a small molecule without mutating its conformation 33 .…”