A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.

/pdf/extra-precision-glide-docking-and-scoring-incorporating-a-2o3e7pl9pg.pdf

Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes

https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.

Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments

Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. In parallel to the terms ‘transcriptome’ and ‘proteome’, the set of metabolites synthesized by a biological system constitute its ‘metabolome’. Yet, unlike other functional genomics approaches, the unbiased simultaneous identification and quantification of plant metabolomes has been largely neglected. Until recently, most analyses were restricted to profiling selected classes of compounds, or to fingerprinting metabolic changes without sufficient analytical resolution to determine metabolite levels and identities individually. As a prerequisite for metabolomic analysis, careful consideration of the methods employed for tissue extraction, sample preparation, data acquisition, and data mining must be taken. In this review, the differences among metabolite target analysis, metabolite profiling, and metabolic fingerprinting are clarified, and terms are defined. Current approaches are examined, and potential applications are summarized with a special emphasis on data mining and mathematical modelling of metabolism.

https://link.springer.com/content/pdf/10.1023%2FA%3A1013713905833.pdf

Metabolomics - the link between genotypes and phenotypes

N-Heterocyclic Carbenes in Late Transition Metal Catalysis

Regiospecific and asymmetric introduction of functionalized branching in carbohydrates

Synthesis of aminocyclodextrin carboxylic acids (6-amino-6′-carboxylic acid) via selective amination and oxidation of 6 A ,6 D -dihydroxy α- and β-cyclodextrins, respectively, is reported.

Synthesis of Aminocyclodextrin Carboxylic Acids

Herein we describe synthetic efforts toward the total synthesis of calyciphylline B-type alkaloids. In the process, we disclose a detailed DFT study of equilibrium geometries and transition states that explains the stereochemical outcome during the formation of critical intermediates. X-ray crystallographic analysis reveals interesting conformational features in the naturally occurring deoxycalyciphylline B and its synthetic congeners.

Strategies toward the Total Synthesis of Calyciphylline B-type Alkaloids: A Computational Perspective Aided by DFT Analysis

Conformation of MurNAc-L-Ala-D-iGln (MDP) and of a constrained analog using 1H NMR data and molecular modeling

C2-symmetrical bis(oxazoline) ligands bearing pendant alkylthio ether groups were synthesized, and the structures of Cu complexes were determined by single crystal X-ray diffraction. The potential ...

Stephen Hanessian

Papers

Regiospecific and asymmetric introduction of functionalized branching in carbohydrates

Synthesis of Aminocyclodextrin Carboxylic Acids

Strategies toward the Total Synthesis of Calyciphylline B-type Alkaloids: A Computational Perspective Aided by DFT Analysis

Conformation of MurNAc-L-Ala-D-iGln (MDP) and of a constrained analog using 1H NMR data and molecular modeling

Bifunctional bis(oxazolines) as potential ligands in catalytic asymmetric reactions