Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function

Abstract

The HYDE scoring function consistently describes hydrogen bonding, the hydrophobic effect and desolvation. It relies on HYdration and DEsolvation terms which are calibrated using octanol/water partition coefficients of small molecules. We do not use affinity data for calibration, therefore HYDE is generally applicable to all protein targets. HYDE reflects the Gibbs free energy of binding while only considering the essential interactions of protein-ligand complexes. The greatest benefit of HYDE is that it yields a very intuitive atom-based score, which can be mapped onto the ligand and protein atoms. This allows the direct visualization of the score and consequently facilitates analysis of protein-ligand complexes during the lead optimization process. In this study, we validated our new scoring function by applying it in large-scale docking experiments. We could successfully predict the correct binding mode in 93% of complexes in redocking calculations on the Astex diverse set, while our performance in virtual screening experiments using the DUD dataset showed significant enrichment values with a mean AUC of 0.77 across all protein targets with little or no structural defects. As part of these studies, we also carried out a very detailed analysis of the data that revealed interesting pitfalls, which we highlight here and which should be addressed in future benchmark datasets.

Imidazolylchromanones containing alkyl side chain as lanosterol 14α-demethylase inhibitors: synthesis, antifungal activity and docking study

“…Theoretically, the fused six-membered hetero-ring of chroman moiety can exist in the form of two energetically different half-chairs in which 2-alkyl side chain and 3-imidazolyl moiety occupy di-axial or di-equatorial positions ( Figure 6). The relatively large J 2,3 value in compound 4d prototype confirms the preferred di-axial conformation of H-2 and H-3 15 . Thus, it is believed that 2-alkyl side chain and 3-imidazolyl moiety in compound 4d exist predominantly in the di-equatorial conformation.…”

“…The binding site was defined to any residues 8 Å distant from the co-crystallized fluconazole in the complex crystal structure of the enzyme. For an evaluation of the ligands affinity towards active site, the HYDE assessment module of LeadIT software was used to report the free energy of binding (DG) and ligand efficiency of the best scored pose 14,15 .…”

“…HYDE is an empirical scoring function, which assesses protein-ligand complex by considering hydrogen bond interactions and also hydrophobic and desolvation effects and provides estimation for the binding affinity 14,15 . For the (SS)-enantiomeric form of 5d (with DG binding ¼ À42 kJ/mol), hydrogen bonding seems to be more possible between the oxime hydrogen atom and carbonyl oxygen atom of Phe255 (3 Å ).…”

Physics-Based Visual Characterization of Molecular Interaction Forces

“…Some software packages provide means to overlap a set of semitransparent spheres around atoms, used to color encode atom properties, e.g., Coulomb charges or hydrophobicity, such as in Vesta [35,36]. The Hyde software color codes atoms according to their total affinity energy contribution [45], whereby the process takes several seconds. Günter et al also focus on the atom level, where the signed electron density and reduced gradient fields are computed and then simplified to illustrate van der Waals and steric repulsion forces between atoms [17].…”

Molecular Identification of d-Ribulokinase in Budding Yeast and Mammals

“…Because the ligand D-xylulose was included in the template crystal structure for FGGY (PDB code 3L0Q), but not in the template providing the best scored structural model for Ydr109c (PDB code 3GG4), molecular docking simulations with this ligand were performed in the Ydr109c structure using the software LeadIT/FlexX (version 2.1.5) (78). The top 30 docking poses were then determined, and binding affinity estimates were calculated for each pose by applying the LeadIT/HYDE tool (79). More details on the used docking pipeline can be found in Ref.…”