We propose a novel approach to deriving partial atomic charges from population analysis. The new model, called Charge Model 5 (CM5), yields class IV by mapping those obtained Hirshfeld analysis of density functional electronic charge distributions. CM5 model utilizes single set parameters derived fitting reference values the gas-phase dipole moments 614 molecular structures. An additional test (not included in parametrization) contained 107 singly charged ions with nonzero moments,...

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

Epik version 7 is a software program that uses machine learning for predicting the pKa values and protonation state distribution of complex, druglike molecules. Using an ensemble atomic graph convolutional neural networks (GCNNs) trained on over 42,000 across broad chemical space from both experimental computed origins, model predicts with 0.42 0.72 unit median absolute root mean square errors, respectively, seven test sets. also generates states recovers 95% most populated compared to...

We present a reliable and accurate solution to the induced fit docking problem for protein–ligand binding by combining ligand-based pharmacophore docking, rigid receptor protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective prospective testing succeeded determine modes root-mean-square deviation within 2.5 Å over 90% of cross-docking cases. further demonstrate these predicted ligand–receptor structures were...

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

The recently developed AlphaFold2 (AF2) algorithm predicts proteins’ 3D structures from amino acid sequences. open AlphaFold protein structure database covers the complete human proteome. Using an industry-leading molecular docking method (Glide), we investigated virtual screening performance of 37 common drug targets, each with AF2 and known holo apo DUD-E data set. In a subset 27 targets where are suitable for refinement, show comparable early enrichment active compounds (avg. EF 1%: 13.0)...

We have developed a new methodology for protein–ligand docking and scoring, WScore, incorporating flexible description of explicit water molecules. The locations thermodynamics the waters are derived from WaterMap molecular dynamics simulation. structure is employed to provide an atomic level ligand protein desolvation. WScore also contains detailed model localized strain energy integrates MM-GBSA scoring component with these terms assess delocalized complex. Ensemble used take into account...

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

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 chemical space that can be difficult access synthetically. ratio macrocycle dimer, generated via copper catalyzed azide–alkyne cycloaddition macrocyclization in flow at elevated temperature, could rationalized terms the energy macrocyclic product. progressive increase resulting from reduction ring...

The recently developed AlphaFold2 (AF2) algorithm predicts proteins’ 3D structures from amino acid sequences. open AlphaFold Protein Structure Database covers the complete human proteome. It shows great potential to provide structural information enable and enhance existing new drug discovery projects. Using an industry-leading molecular docking method (Glide), we benchmarked virtual screening performance of 28 common targets each with AF2 structure known holo apo DUD-E dataset. show...

Relative binding free energy (RBFE) prediction methods such as perturbation (FEP) are important today for estimating protein–ligand affinities. Significant hardware and algorithmic improvements now allow simulating congeneric series within days. Therefore, RBFE calculations have an enormous potential structure-based drug discovery. As typically only a few representative crystal structures available, other ligands design proposals must be reliably superimposed meaningful results. An observed...

While large library docking has discovered potent ligands for multiple targets, as the libraries have grown 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 cross-filters. In retrospective studies, this approach deprioritized high-ranking nonbinders nine targets while...

Ribonucleic acids (RNAs) are emerging as important drug targets, yet in silico modeling of RNA-small molecule interactions presents unique challenges compared to protein targets. This study evaluates and improves computational tools within the Schrödinger Suite for hit discovery against RNA. We benchmarked enhanced SiteMap identifying RNA binding sites, introducing an RNA-specific scoring function that improved site prediction accuracy from 44.4% 65.3% on a filtered HARIBOSS dataset. also...

Ribonucleic acids (RNAs) are emerging as important drug targets, yet in silico modeling of RNA-small molecule interactions presents unique challenges compared to protein targets. This study evaluates and improves computational tools within the Schrödinger Suite for hit discovery against RNA. We benchmarked enhanced SiteMap identifying RNA binding sites, introducing an RNA-specific scoring function that improved site prediction accuracy from 44.4% 65.3% on a filtered HARIBOSS dataset. also...

Unlike normal Diels–Alder reactions of acyclic alkadienes with alkenes, the vinylbicyclo[2.2.2]octene employed in Baran total synthesis vinigrol undergoes a quantitative reaction tethered alkene at room temperature. Density functional theory calculations reveal that this unprecedented reactivity originates from combination preorganization, diene strain, and tether stabilization.

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

Lpd (lipoamide dehydrogenase) in Mycobacterium tuberculosis (Mtb) is required for virulence and a genetically validated (TB) target. Numerous screens have been performed over the last decade, yet only two inhibitor series identified. Recent advances large-scale virtual screening methods combined with make-on-demand compound libraries shown potential finding novel hits. In this study, Enamine REAL library consisting of ∼1.12 billion compounds was efficiently screened using GPU Shape screen...

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 theory. These results then scaled, primarily to correct basis set effects (as in previous work on predicting pKa's organic systems1-5). Finally, localized orbital corrections (LOCs), developed by fitting properties such as ionization potentials, electron affinities, and ligand removal energies prior...

Epik version 7 is a software program that uses machine learning for predicting the pKa values and protonation state distribution of complex, drug-like molecules. Using an ensemble atomic graph convolutional neural networks (GCNNs) trained on over 42,000 across broad chemical space from both experimental computed origins, model predicts with 0.42 0.72 log unit median absolute RMS errors, respectively, seven test sets. also generates states recovers 95% most populated compared to previous...

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore (Phase), rigid receptor (Glide), protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. provide an in-depth description of our novel methodology results 41 targets consisting 415 cross-docking cases divided amongst training test set. For both test-set, we compute modes ligand-heavy atom RMSD within 2.5 Å or...

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

The recently developed AlphaFold2 (AF2) algorithm predicts proteins’ 3D structures from amino acid sequences. open AlphaFold Protein Structure Database covers the complete human proteome. It shows great potential to provide structural information enable and enhance existing new drug discovery projects. Using an industry-leading molecular docking method (Glide), we benchmarked virtual screening performance of 28 common targets each with AF2 structure known holo apo DUD-E dataset. show...

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