Identifying Artifacts from Large Library Docking.

While large library docking has discovered potent ligands for multiple targets, as the libraries have grown the hit lists can become dominated by rare artifacts that cheat our scoring functions. Here, we investigate rescoring top-ranked docked molecules with orthogonal methods to identify these artifacts, exploring implicit solvent models and absolute binding free energy perturbation as cross-filters. In retrospective studies, this approach deprioritized high-ranking nonbinders for nine targets while leaving true ligands relatively unaffected.

Identifying Artifacts from Large Library Docking.

While large library docking has discovered potent ligands for multiple targets, as the libraries have grown, the very top of the hit-lists can become populated with artifacts that cheat our scoring functions. Though these cheating molecules are rare, they become ever-more dominant with library growth. Here, we investigate rescoring top-ranked molecules from docking screens with orthogonal methods to identify these artifacts, exploring implicit solvent models and absolute binding free energy perturbation (AB-FEP) as cross-filters.

Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase Inhibitors.

Lpd (lipoamide dehydrogenase) in (Mtb) is required for virulence and is a genetically validated tuberculosis (TB) target. Numerous screens have been performed over the last decade, yet only two inhibitor series have been identified. Recent advances in large-scale virtual screening methods combined with make-on-demand compound libraries have shown the potential for finding novel hits.

Enhancing Hit Discovery in Virtual Screening through Absolute Protein-Ligand Binding Free-Energy Calculations.

In the hit identification stage of drug discovery, a diverse chemical space needs to be explored to identify initial hits. Contrary to empirical scoring functions, absolute protein-ligand binding free-energy perturbation (ABFEP) provides a theoretically more rigorous and accurate description of protein-ligand binding thermodynamics and could, in principle, greatly improve the hit rates in virtual screening. In this work, we describe an implementation of an accurate and reliable ABFEP method in FEP+.

Epik: p and Protonation State Prediction through Machine Learning.

Epik version 7 is a software program that uses machine learning for predicting the p values and protonation state distribution of complex, druglike molecules. Using an ensemble of atomic graph convolutional neural networks (GCNNs) trained on over 42,000 p values across broad chemical space from both experimental and computed origins, the model predicts p values with 0.42 and 0.

Benchmarking Refined and Unrefined AlphaFold2 Structures for Hit Discovery.

The recently developed AlphaFold2 (AF2) algorithm predicts proteins' 3D structures from amino acid sequences. The open AlphaFold protein structure database covers the complete human proteome. Using an industry-leading molecular docking method (Glide), we investigated the virtual screening performance of 37 common drug targets, each with an AF2 structure and known and structures from the DUD-E data set.

Efficient Exploration of Chemical Space with Docking and Deep Learning.

With the advent of make-on-demand commercial libraries, the number of purchasable compounds available for virtual screening and assay has grown explosively in recent years, with several libraries eclipsing one billion compounds. Today's screening libraries are larger and more diverse, enabling the discovery of more-potent hit compounds and unlocking new areas of chemical space, represented by new core scaffolds. Applying physics-based in silico screening methods in an exhaustive manner, where every molecule in the library must be enumerated and evaluated independently, is increasingly cost-prohibitive.

Evaluation of the Performance of the B3LYP, PBE0, and M06 DFT Functionals, and DBLOC-Corrected Versions, in the Calculation of Redox Potentials and Spin Splittings for Transition Metal Containing Systems.

We have evaluated the performance of the M06 and PBE0 functionals in their ability to calculate spin splittings and redox potentials for octahedral complexes containing a first transition metal series atom. The mean unsigned errors (MUEs) for these two functionals are similar to those obtained for B3LYP using the same data sets. We then apply our localized orbital correction approach for transition metals, DBLOC, in an effort to improve the results obtained with both functionals.

Successful application of the DBLOC method to the hydroxylation of camphor by cytochrome p450.

The activation barrier for the hydroxylation of camphor by cytochrome P450 was computed using a mixed quantum mechanics/molecular mechanics (QM/MM) model of the full protein-ligand system and a fully QM calculation using a cluster model of the active site at the B3LYP/LACVP*/LACV3P** level of theory, which consisted of B3LYP/LACV3P** single point energies computed at B3LYP/LACVP* optimized geometries. From the QM/MM calculation, a barrier height of 17.5 kcal/mol was obtained, while the experimental value was known to be less than or equal to 10 kcal/mol.

Accurate pKa prediction in first-row hexaaqua transition metal complexes using the B3LYP-DBLOC method.

Acid dissociation constants are computed with density functional theory (DFT) for a series of ten first-row octahedral hexaaqua transition metal complexes at the B3LYP/LACV3P** level of theory. These results are then scaled, primarily to correct for basis set effects (as in previous work on predicting pKa's in organic systems1-5). Finally, localized orbital corrections (LOCs), developed by fitting properties such as ionization potentials, electron affinities, and ligand removal energies in prior publications,3,4,6,7 are applied without any further parameter adjustment.

Why a proximity-induced Diels-Alder reaction is so fast.

Unlike normal Diels-Alder reactions of acyclic alkadienes with alkenes, the vinylbicyclo[2.2.2]octene employed in the Baran total synthesis of vinigrol undergoes a quantitative Diels-Alder reaction with a tethered alkene at room temperature.

Charge Model 5: An Extension of Hirshfeld Population Analysis for the Accurate Description of Molecular Interactions in Gaseous and Condensed Phases.

We propose a novel approach to deriving partial atomic charges from population analysis. The new model, called Charge Model 5 (CM5), yields class IV partial atomic charges by mapping from those obtained by Hirshfeld population analysis of density functional electronic charge distributions. The CM5 model utilizes a single set of parameters derived by fitting to reference values of the gas-phase dipole moments of 614 molecular structures.

Strained cyclophane macrocycles: impact of progressive ring size reduction on synthesis and structure.

The synthesis, X-ray crystal structures, and calculated strain energies are reported for a homologous series of 11- to 14-membered drug-like cyclophane macrocycles, representing an unusual region of chemical space that can be difficult to access synthetically. The ratio of macrocycle to dimer, generated via a copper catalyzed azide-alkyne cycloaddition macrocyclization in flow at elevated temperature, could be rationalized in terms of the strain energy in the macrocyclic product. The progressive increase in strain resulting from reduction in macrocycle ring size, or the introduction of additional conformational constraints, results in marked deviations from typical geometries.