Towards an Integrated Description of Hydrogen Bonding and Dehydration: Decreasing False Positives in Virtual Screening with the HYDE Scoring Function

Abstract

We developed a new empirical scoring function, HYDE, for the evaluation of protein-ligand complexes. HYDE estimates binding free energy based on two terms for dehydration and hydrogen bonding only. The essential feature of this scoring function is the integrated use of log P-derived atomic increments for the prediction of free dehydration energy and hydrogen bonding energy. Taking the dehydration of atoms within the interface into account shows that some atoms contribute favorably to the overall score, while others contribute unfavorably. For instance, hydrogen bond functions are penalized if they are dehydrated unless they can overcompensate this loss by forming a hydrogen bond with excellent geometry. The main stabilizing contribution represents the removal of apolar groups from the water: the hydrophobic effect. Initial studies using the DUD dataset show that with HYDE, there is a significant decrease in false positives, a reasonable categorization of compounds as either non-binders, weak, medium or strong binders, and in particular, there is a generally applicable and thermodynamically sensible cutoff score below which there is a high likelihood that the compound is indeed a binder.

Molecular Docking and Structure-Based Drug Design Strategies

“…Empirical Knowledge-Based DOCK [32] AutoDock [34] SMoG [82] AutoDock [34] GlideScore [37] DrugScore [62] GoldScore [35] ChemScore [60] PMF_Score [83] ICM [46] X_Score [66] MotifScore [84] LigandFit [47] F_Score [73] RF_Score [85] Molegro Virtual Docker [48] Fresno [75] PESD_SVM [86] SYBYL_G-Score [73] SCORE [76] PoseScore [87] SYBYL_D-Score [73] LUDI [77] MedusaScore [74] SFCscore [78] HYDE [79] LigScore [80] PLP [81] …”

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

“…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 ).…”

Predictive Modeling of Molecular Properties: Can We Go beyond Interpretation?

“…The question therefore arises as to why a separate force field is needed for docking (apart from saving CPU-time for very high-throughput applications). Recently, docked poses have been refined using a development of the Merck force field in order to improve predictions [74]. A further necessary step would be to perform MD simulations of the ligand-receptor combination in order to improve sampling and provide a solid basis for calculations of the entropic contribution to binding.…”

“…Rational approaches that emphasize the predominantly hydrophobic nature of binding [74] are still rare, and most scoring functions still emphasize local, specific interactions that in many cases are most likely to be responsible for selectivity, rather than increasing the binding strength. An accurate assessment of the ability to score protein-ligand binding at present is that it is usually unsuccessful [77,78].…”