Two-track virtual screening approach to identify both competitive and allosteric inhibitors of human small C-terminal domain phosphatase 1

Abstract

Despite a wealth of persuasive evidence for the involvement of human small C-terminal domain phosphatase 1 (Scp1) in the impairment of neuronal differentiation and in Huntington's disease, small-molecule inhibitors of Scp1 have been rarely reported so far. This study aims to the discovery of both competitive and allosteric Scp1 inhibitors through the two-track virtual screening procedure. By virtue of the improvement of the scoring function by implementing a new molecular solvation energy term and by reoptimizing the atomic charges for the active-site Mg ion cluster, we have been able to identify three allosteric and five competitive Scp1 inhibitors with low-micromolar inhibitory activity. Consistent with the results of kinetic studies on the inhibitory mechanisms, the allosteric inhibitors appear to be accommodated in the peripheral binding pocket through the hydrophobic interactions with the nonpolar residues whereas the competitive ones bind tightly in the active site with a direct coordination to the central Mg ion. Some structural modifications to improve the biochemical potency of the newly identified inhibitors are proposed based on the binding modes estimated with docking simulations.

Targeting the C-Terminal Domain Small Phosphatase 1

“…Similarly, CTDSP1 also has a conserved structure and similar activity to other CTDSPs. We observed that CTDSP1 also possesses characteristics from co-crystallized ligand experiments and a unique hydrophobic site adjacent to the active site, shown in Figure 3, which helps the inhibitor to bind to CTDSP1 without affecting catalytic residues [17,18]. Interestingly, CTDNEP1, as one of the conserved paralogs, was not affected by the ligand rabeprazole as much as CTDSP1 [17].…”

“…In earlier studies [17,18], researchers emphasized the structural complexity in targeting CTDSP as the significant bottleneck; hence, in this section, we are going to address the structural barriers and privileges of CTDSP1 as a successful biological target. The major challenge in targeting CTDSP1 is the conserved structures of CTDSP ( Figure 2).…”

“…Finely determined X-ray structures (PDB ID: 2GHT, 2GHQ, 3PGL, 4YH1, 4YGY) are available for CTDSP1 in the PDB database. The essential requirement for structure-based drug design [131], which has also been considered in a few earlier studies [17,18], is the need to target precisely the successive regulation of CTDSP1. Previous studies can also help us to understand the essence of the combinatorial approach in the successful identification of novel small molecules for CTDSP1 as a drug target.…”

“…However, we agree that there could be yet unexplored, better docking methods than allosteric docking and ensemble docking in the targeting of CTDSP1. [17,18,153] for targeting CTDSP1. The left square represents conventional docking, which targets the active site of human CTDSP1.…”

“…There are a few challenges in targeting CTDSP1 despite its potential. In previous studies [17][18][19], researchers tried to identify chemical inhibitors targeting human CTDSP1 and emphasized structure-related bottlenecks, which must be solved to develop very specifically targeting drugs for CTDSP1. Structure-based drug design has become a handy tool to solve many complex problems, such as handling the big data of combinatorial synthesis, improving the structure of multitarget drug molecules, dealing with the structural similarity of target proteins, and finding a perfect fit of drug molecules for target proteins in the drug discovery process [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”