Pharmacophore modeling and molecular dynamics simulation to identify the critical chemical features against human sirtuin 2 inhibitors

Sirtuin 2 (SIRT2) is one of the emerging targets in chemotherapy field and mainly associated with many diseases such as cancer and Parkinson’s. Hence, quantitative hypothesis was developed using Discovery Studio v2.5. Top ten resultant hypotheses were generated, among them Hypo1 was selected as a best hypothesis based on the statistical parameters like high cost difference (52), lowest RMS (0.71), and good correlation coefficient (0.96). Hypo1 has been validated by using well known methodologies such as Fischer’s randomization method (95% confidence level), test set which has shown the correlation coefficient of 0.93 as well as the goodness of hit (0.65), and enrichment factor (8.80). All the above statistical validations confirm that the chemical features in Hypo1 (1 hydrogen bond acceptor, 1 hydrophobic, and 2 ring aromatic features) was able to inhibit the function of SIRT2. Hence, Hypo1 was used as a query in virtual screening to find a novel scaffolds by screening the various chemical databases. The screened molecules from the databases were checked for the ADMET as well as the drug-like properties. Due to the lack of SIRT2–ligand complex structure in PDB, molecular docking and molecular dynamics (MD) simulation was carried out to find the suitable orientation of ligand in the active site. The representative structure from MD simulations was used as a receptor to dock the molecules which passed the drug-like properties from the virtual screening. Finally, 29 compounds were selected as a potent candidate leads based on the interactions with the active site residues of SIRT2. Thus, the resultant pharmacophore can be used to discover and design the SIRT2 inhibitors with desired biological activity.

► 3D hypotheses were generated and validated using various potent methods.
► Hypo1 was selected as best hypothesis based on its statistical parameters.
► Hypo1, used as query in virtual screening and hits are sorted by drug-like property.
► Absence of SIRT2 complex structure, docking and molecular simulation was carried out.
► Representative structure from molecular dynamics was used to dock the hit leads.