Ligand Pose and Orientational Sampling in Molecular Docking

Abstract

Molecular docking remains an important tool for structure-based screening to find new ligands and chemical probes. As docking ambitions grow to include new scoring function terms, and to address ever more targets, the reliability and extendability of the orientation sampling, and the throughput of the method, become pressing. Here we explore sampling techniques that eliminate stochastic behavior in DOCK3.6, allowing us to optimize the method for regularly variable sampling of orientations. This also enabled a focused effort to optimize the code for efficiency, with a three-fold increase in the speed of the program. This, in turn, facilitated extensive testing of the method on the 102 targets, 22,805 ligands and 1,411,214 decoys of the Directory of Useful Decoys - Enhanced (DUD-E) benchmarking set, at multiple levels of sampling. Encouragingly, we observe that as sampling increases from 50 to 500 to 2000 to 5000 to 20000 molecular orientations in the binding site (and so from about 1×1010 to 4×1010 to 1×1011 to 2×1011 to 5×1011 mean atoms scored per target, since multiple conformations are sampled per orientation), the enrichment of ligands over decoys monotonically increases for most DUD-E targets. Meanwhile, including internal electrostatics in the evaluation ligand conformational energies, and restricting aromatic hydroxyls to low energy rotamers, further improved enrichment values. Several of the strategies used here to improve the efficiency of the code are broadly applicable in the field.

Testing inhomogeneous solvation theory in structure-based ligand discovery

“…Following convention, negative GIST energies reflect favorable, costly-todisplace waters. We used adjusted logAUC to measure docking enrichment (39,(42)(43)(44)(45); this metric weights each factor of 10 in docking rank order equally, beginning from the top 0.1%, prioritizing the performance of the very top ranking ligands or decoys in the docking screen (44). Scaled enthalpy performed the best (adjusted logAUC of 57.46 ± 1.84), closely followed by unscaled free energy (56.08 ± 1.42).…”

Determinants of Substrate and Cation Transport in the Human Na+/Dicarboxylate Cotransporter NaDC3

“…Molecular Docking-Docking of NaDC3 substrates was performed with DOCK 3.5.54 (30,26), which calculates scores of docking poses with van der Waals, Poisson-Boltzmann electrostatic, and substrate desolvation penalty terms. The transporter model with refined side chains was prepared by removing all non-protein atoms except for the sodium ion.…”

“…The transporter model with refined side chains was prepared by removing all non-protein atoms except for the sodium ion. Binding site residues were identified as residues with at least one atom within 10 Å of any heavy atoms of the ligand citrate from the initial model using the program FILT (from the DOCK 3.5 distribution) (30).…”

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6receptor antagonists and beyond

“…[62][63][64] In this case, energy minimization of the system is required, but in our experience, many force elds neglect the conformational preferences based on weak intramolecular interactions and oen lead to unrealistic ligand geometries.…”