Design and development of novel potential inhibitors of the human USP21 enzyme using a pharmacophore-based virtual...

An overexpression and increase have been observed in the concentration and activity of the ubiquitin-specific protease 21 (USP21) enzyme in many cancers, necessitating the need for the development of new inhibitor drugs against the same. The current study attempts to discover one such novel potential inhibitor of USP21 by the application of various bioinformatics techniques which include molecular modeling, pharmacophore mapping, pharmacophore-based virtual screening, molecular docking, and ADMET prediction followed by molecular dynamics simulations. Following this inverted funnel-like approach, we finally ended up with one ligand-ZINC02422616 which displays a very high binding affinity toward the USP21 domain. This ligand contains all the pharmacophoric features displayed by the compounds that are potential inhibitors of the USP21 domain. Moreover, it shows a favorable pharmacokinetic, pharmacodynamic, and ADMET profile, along with strong hydrophobic interaction and hydrogen bonding with the domain. Simulation studies showed that the complex remains stable over time, with the bound protein displaying a more constrained motion in the conformational space compared to the unbound form. The ligand showed a highly favorable free energy landscape/surface, forming several energy minima's in contrast to the unbound domain in which most conformations occupied a relatively higher energy state. Moreover, the ligand also displayed a K_d of 422.8 nM and a free energy of binding ΔG of -8.6 kcal/mol, both of which indicate a very high affinity toward the target domain. This potential drug candidate can then be used as a viable treatment method for many types of cancers caused by USP21.