Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors

Abstract

Metalloenzymes are ubiquitous proteins which feature one or more metal ions either directly involved in the enzymatic activity and/or structural properties (i.e., zinc fingers). Several members of this class take advantage of the Lewis acidic properties of zinc ions to carry out their various catalytic transformations including isomerization or amide cleavage. These enzymes have been validated as drug targets for a number of diseases including cancer; however, despite their pharmaceutical relevance and the availability of crystal structures, structure-based drug design methods have been poorly and indirectly parametrized for these classes of enzymes. More specifically, the metal coordination component and proton transfers of the process of drugs binding to metalloenzymes have been inadequately modeled by current docking programs, if at all. In addition, several known issues, such as coordination geometry, atomic charge variability, and a potential proton transfer from small molecules to a neighboring basic residue, have often been ignored. We report herein the development of specific functions and parameters to account for zinc-drug coordination focusing on the above-listed phenomena and their impact on docking to zinc metalloenzymes. These atom-type-dependent but atomic charge-independent functions implemented into Fitted 3.1 enable the simulation of drug binding to metalloenzymes, considering an acid-base reaction with a neighboring residue when necessary with good accuracy.

AutoDock4Zn: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins

“…7 Recently, DFT calculations were used to calibrate a nondirectional zinc coordination force field independent of atomic partial charges. 19 …”

Integrating Structure and Ligand-Based Approaches for Modelling the Histone Deacetylase Inhibition Activity of Hydroxamic Acid Derivatives

“…2a). Especially, the similarly close distances (<2.5 Å) between hydroxamate groups and zinc ion, which play an important role in the zinc-binding motif of HDAC inhibitors [34], are conserved. Considering these results, our protocol is suitable for using in further docking experiments.…”

“…All water molecules were removed, and the polar hydrogen atoms were aided to the protein. The active site of the enzyme includes key residues His145, His146, Asp181, His183, and Asp269, which were appropriately protonated according to the general catalytic transformations of zinc metalloenzymes described by Pottel et al [34]. Afterward, the binding site was energy minimized applying AMBER99 force field based on truncated Newton method in MOE (convergence criteria of 0.01 Å root-mean-square deviation [RMSD]) [31].…”

Optimization of histone deacetylase inhibitor activity in non-secosteroidal vitamin D-receptor agonist hybrids

“…The linker spans a narrow access tube and is most commonly a straight-chain aliphatic linker. Using FITTED, a docking software that has been recently parameterized for HDACs, 18 we docked JF-B01 in HDAC2, chosen due to high homology to HDAC3 and the availability of several Xray crystal structures. 19 As expected, the short aliphatic ether in JF-B01 is insufficient to fully span the access tube and thus one aromatic ring must be part of the linker, with the diethyl pentane and second aromatic making contacts at the surface (Fig.…”