In silico identification of A1 agonists and A2a inhibitors in pain based on molecular docking strategies and dynamics simulations

Abstract

Most recently, the adenosine is considered as one of the most promising targets for treating pain, with few side effects. It exists in the central nervous system, and plays a key role in nociceptive afferent pathway. It is reported that the A1 receptor (A1R) could inhibit Ca²⁺ channels to reduce the pain like analgesic mechanism of morphine. And, A2a receptor (A2aR) was reported to enhance the accumulation of AMP (cAMP) and released peptides from sensory neurons, resulting in constitutive activation of pain. Much evidence showed that A1R and A2aR could be served as the interesting targets for the treatment of pain. Herein, virtual screening was utilized to identify the small molecule compounds towards A1R and A2aR, and top six molecules were considered as candidates via amber scores. The molecular dynamic (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) were employed to further analyze the affinity and binding stability of the six molecules towards A1R and A2aR. Moreover, energy decomposition analysis showed significant residues in A1R and A2aR, including His1383, Phe1276, and Glu1277. It provided basics for discovery of novel agonists and antagonists. Finally, the agonists of A1R (ZINC19943625, ZINC13555217, and ZINC04698406) and inhibitors of A2aR (ZINC19370372, ZINC20176051, and ZINC57263068) were successfully recognized. Taken together, our discovered small molecules may serve as the promising candidate agents for future pain research.

Keywords: Adenosine A1 receptor; Adenosine A2a receptor; Drug discovery; Pain; Potential agents.

Fig. 1

HYPERLINK "sps:id::fig1||locator::gr1||MediaObject::0" 3D structure of the docking small molecule with A1R in the crystallographic complex

Fig. 2

3D structure of the docking small molecule with A2aR in the crystallographic complex

Fig. 3

The 2D structure of receptor-ligand interaction of molecule with A1R

Fig. 4

The 2D structure of receptor-ligand interaction of molecule with A2aR

Fig. 5

The RMSD results of A1 adenosine receptor-ligand complexes with the pain agonist (A–B) and the A2a adenosine receptor-ligand complexes with the pain antagonist (C–D)

Fig. 6

The RMSF results of A1 adenosine receptor-ligand complexes with the pain agonist (A–B), and the A2a adenosine receptor-ligand complexes with the pain antagonist (C–D)

Fig. 7

Binding free energy decomposition on per residue of A1 adenosine receptor-ligand complex

Fig. 8

Binding free energy decomposition on per residue of A2a adenosine receptor-ligand complexes