10 Duvelisib Lies Unwrapped

252 for compound AsXE1. It was reported that the best scoring compounds contained a mercapto group and a triazole or tetrazole ring in the scaffold. The relevant moieties, triazole and tetrazole, most likely interact with R58, L119, and R136 residues and Duvelisib mimic key interactions of the enzyme�Csubstrate complex, specifically the interaction of these residues with the carboxyl group of shikimate. Two of the nitrogen atoms of the azole system were hydrogen bonded to R58 and R136 and the proximity of the L119 with the heteroaromatic ring, suggesting the possibility of stabilizing CH�Celectron interactions.26 The mercapto group interacted with G80, R117, and L119 through hydrophobic forces and hydrogen bonds. The interaction with R117 is key for the phosphoryl transfer reaction catalyzed by MtSK.26 Of the 644 molecules, the 200 top-scoring compounds were analyzed to determine the main interactions that were occurring between the compound and the binding site. Hydrophobic forces were seen with residues P11, K15 (P-loop), D34, I45, F49, F57 (NMP-binding domain), G79, G80 (Walker-B motif), G81 (C-terminal to the Walker-B motif), V116, R117, P118, and L119 (lid domain). Additionally, hydrogen bonding with Bleomycin residues D34, R58 (NMP-binding domain), G80 (Walker-B motif), G81, V116, R117, L119 (lid domain), and R136 were observed (Table 3).26 Table 3 eHiTS scores and molecular structures for controls and top compounds. Molecular docking of known inhibitors A total of 33 known inhibitors of MtSK were analyzed against the 3D model of SK from ESyPred3D27 using Schrodinger docking software. The 3D model from ESyPred3D was used because when superimposed with the crystal structure of MtSK from Dali Pairwise Comparison, PDB ID: 2IYT, this predicted model had the lowest RMSD value, suggesting a highly accurate model. The docking scores for the top 10 compounds are given (Table 4) with the best docking score being �C6.174338 for compound SPB01099 versus �C6.138796 for control shikimate.28 Table 4 Docking scores of the top 10 MtSK inhibitors for ESyPred3D model. Shikimic acid analogs Using structural and molecular dynamics simulation studies, Blanco et al.29 PRDX4 designed shikimic acid analogs that would bind to the shikimate binding site and determined experimental measurements of inhibition constants. Seven shikimic acid analogs (Fig. 4) were assayed and shown to be reversible competitive inhibitors and bind to the same binding site as shikimic acid. The KI values (Table 5), obtained by Dixon plots (1/v vs [I]), ranged from 46 ��M to >4000 ��M with compound 660 being the most potent inhibitor. Figure 4 Molecular structures of shikimic acid analogues. Table 5 KI values of shikimic acid analogs obtained by Dixon plots. The crystal structure of compound 662 interacting with MtSK and ADP was determined at 2.