Molecular Modeling Applied to the Discovery of New Lead Compounds for P2 Receptors Based on Natural Sources

Abstract

P2 receptors are a family of transmembrane receptors activated by nucleotides and nucleosides. Two classes have been described in mammals, P2X and P2Y, which are implicated in various diseases. Currently, only P2Y12 has medicines approved for clinical use as antiplatelet agents and natural products have emerged as a source of new drugs with action on P2 receptors due to the diversity of chemical structures. In drug discovery, in silico virtual screening (VS) techniques have become popular because they have numerous advantages, which include the evaluation of thousands of molecules against a target, usually proteins, faster and cheaper than classical high throughput screening (HTS). The number of studies using VS techniques has been growing in recent years and has led to the discovery of new molecules of natural origin with action on different P2X and P2Y receptors. Using different algorithms it is possible to obtain information on absorption, distribution, metabolism, toxicity, as well as predictions on biological activity and the lead-likeness of the selected hits. Selected biomolecules may then be tested by molecular dynamics and, if necessary, rationally designed or modified to improve their interaction for the target. The algorithms of these in silico tools are being improved to permit the precision development of new drugs and, in the future, this process will take the front of drug development against some central nervous system (CNS) disorders. Therefore, this review discusses the methodologies of in silico tools concerning P2 receptors, as well as future perspectives and discoveries, such as the employment of artificial intelligence in drug discovery.

Keywords: P2 receptors; drug discovery; homology modeling; molecular dynamics; molecular modelling; natural products; virtual screening.

Figure 1

Three-dimensional structures of the closed and open (ATP-bound) P2X4 states. (A, B) Crystal structure of the zfP2X4 (PDB code 4DW0) in different views, apo and open, with the transmembrane helices colored according to the subunit colors in blue, yellow, and green. ATP molecules are displayed as a van der Waals representation. (C) The same structure as in (A), viewed from the top along the axis of the central channel. (D) The same structure as in (B), seen from the top along the axis of the central channel, with ATP bound to the pharmacophore site.

Figure 2

3D structure of P2Y12. The structure in (A, B) represents the P2Y12 (PDB code 4PXZ) crystal in the lateral view. (A) indicates the helix in light brown represents the transmembrane domain of P2Y12 and (B) exhibits the same segments represented in dark blue, light blue, red, yellow, brown, light brown, and green. The intracellular helices are represented in (A) in dark gray and in (B), in gray, light gray, orange and purple. The part of the transmembrane domain that extends to the intracellular space is displayed in yellow and green.

Figure 3

Virtual screening workflow. Virtual screening steps since target identification, usually a protein (right) or the reverse, with the target being the molecule, until the final step of in vitro and in vivo tests.