Information Decay in Molecular Docking Screens against Holo, Apo, and Modeled Conformations of Enzymes

Abstract

Molecular docking uses the three-dimensional structure of a receptor to screen a small molecule database for potential ligands. The dependence of docking screens on the conformation of the binding site remains an open question. To evaluate the information loss that occurs as the active site conformation becomes less defined, a small molecule database was docked against the holo (ligand bound), apo, and homology modeled structures of 10 different enzyme binding sites. The holo and apo representations were crystallographic structures taken from the Protein Data Bank (PDB), and the homology-modeled structures were taken from the publicly available resource ModBase. The database docked was the MDL Drug Data Report (MDDR), a functionally annotated database of 95 000 small molecules that contained at least 35 ligands for each of the 10 systems. In all sites, at least 99% of the molecules in the MDDR were treated as nonbinding decoys. For each system, the holo, apo, and modeled structures were used to screen the MDDR, and the ability of each structure to enrich the known ligands for that system over random selection was evaluated. The best overall enrichment was produced by the holo structure in seven systems, the apo structure in two systems, and the modeled structure in one system. These results suggest that the performance of the docking calculation is affected by the particular representation of the receptor used in the screen, and that the holo structure is the one most likely to yield the best discrimination between known ligands and decoy molecules, but important exceptions to this rule also emerge from this study. Although each of the holo, apo, and modeled conformations led to enrichment of known ligands in all systems, the enrichment did not always rise to a level judged to be sufficient to justify the effort of a docking screen. Using a 20-fold enrichment of known ligands over random selection as a rough guideline for what might be enough to justify a docking screen, the holo conformation of the enzyme met this criterion in eight of 10 sites, whereas the apo conformation met this criterion in only two sites and the modeled conformation in three.

A flexible docking scheme to explore the binding selectivity of PDZ domains

“…It might be expected that the prediction accuracy of the docking calculations decreases with the quality of the receptor from the bound (holo) protein to the unbound (apo) protein to the modeled structures. 83 In the case of the unbound structure of GRIP, its conformation may be adequate to accommodate a ligand. Figure 2(B) displays the comparison of the binding energy score versus RMSD of the docked complex.…”

Virtual Screening Strategies in Drug Design

“…Em alguns casos, a conformação holo só permite bons resultados de simulação com moléculas da base de dados estruturalmente semelhantes ao ligante presente na estrutura resolvida do complexo ligante-receptor, perdendo qualidade em simulações com moléculas com características estruturais distintas e um padrão diferente de ligação. 10,23,85 A conformação apo pode ser inadequada para a acomodação do ligante, pois sítios ativos que apresentam mudanças conformacionais podem ter resíduos em posições que não traduziriam um estado adequado para interagir corretamente com o ligante estudado e, dessa forma, dificultar a obtenção de resultados confiáveis em procedimentos de docagem. As estruturas modeladas, por sua vez, dependendo de sua qualidade podem apresentar resíduos ou suas cadeias laterais em locais impróprios, fato que também dificulta a exatidão do procedimento.…”

Structure-Based Drug Design: Docking and Scoring

“…McGovern and Shoichet also carried out a very interesting study [103]. The focus of this study was the information loss that occurs when the active-site conformation becomes less defined.…”