Automated Docking with Protein Flexibility in the Design of Femtomolar “Click Chemistry” Inhibitors of Acetylcholinesterase

Abstract

The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands.1 Here we describe the application of the program AutoDock2 to the design of a focused library that was used in the “click chemistry in-situ” generation of the most potent non-covalent inhibitor of the enzyme acetylcholinesterase (AChE) yet developed (Kd = ~100 fM).3 AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid sidechains of the target protein.

Improvements, trends, and new ideas in molecular docking: 2012–2013 in review

“…This is achieved by separating the chosen side chains from the rigid portion of the receptor and making them part of the input ligand file, however without freedom to change the translation or orientation. Implementations of this approach were done with both AutoDock 4 [9] and AutoDock Vina. [10] Other recent approaches to account for receptor flexibility include the following: mixed coarse grained/all-atom simulations with pre-calculated protein side chains and explicit treatment of bonded interactions along the backbone; [11] combining IFD with quantum polarized docking to obtain realistic affinity constants and enantioselectivity estimates; [12] IFD by combinatorial rearrangement of binding site side chains, followed by grouping rearranged residues in sterically independent families and side-chain conformer clustering; [13] fast, graph-based optimization algorithm for assignment of the near-optimal set of residue rotamers; [14] and efficient multistage backbone reconstruction algorithm for loop regions in receptors.…”

Understanding the challenges of protein flexibility in drug design

“…In some methods, the ligand's pose is optimized before varying the protein side-chains [49], while in more recent methods, both the ligand and side-chain conformations are explored simultaneously [50], [51]. The latter methods have demonstrated significant improvement over rigid-protein docking [52], [53]. Unfortunately, limiting protein flexibility to side chains can sometimes produce worse results than keeping the protein rigid [54].…”

Inhibitors of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] identified by in silico molecular docking

“…Although inhibitors of aminoglycoside acetyltransferases have been described, none potent and efficient enough to be used in the clinics is already available 15–17 . Computational methods have been used to identify or design compounds that bind the active sites of enzymes and inhibit their activity 18–20 . Here we describe inhibitors of AAC(6′)-Ib that were selected by testing compounds selected with in-silico molecular docking.…”