Comparison of topological, shape, and docking methods in virtual screening

Virtual screening benchmarking studies were carried out on 11 targets to evaluate the performance of three commonly used approaches: 2D ligand similarity (Daylight, TOPOSIM), 3D ligand similarity (SQW, ROCS), and protein structure-based docking (FLOG, FRED, Glide). Active and decoy compound sets were assembled from both the MDDR and the Merck compound databases. Averaged over multiple targets, ligand-based methods outperformed docking algorithms. This was true for 3D ligand-based methods only when chemical typing was included. Using mean enrichment factor as a performance metric, Glide appears to be the best docking method among the three with FRED a close second. Results for all virtual screening methods are database dependent and can vary greatly for particular targets.     

Strain localization in an oscillating Maxwell viscoelastic cylinder

The transient rotation responses of simple, axisymmetric, viscoelastic structures are of interest for interpretation of experiments designed to characterize materials and closed structures such as the brain using magnetic resonance techniques. Here, we studied the response of a Maxwell viscoelastic cylinder to small, sinusoidal displacement of its outer boundary. The transient strain field can be calculated in closed form using any of several conventional approaches. The solution is surprising: the strain field develops a singularity that appears when the wavefront leaves the center of the cylinder, and persists as the wavefront reflects to the outer boundary and back to the center of the cylinder. The singularity is alternately annihilated and re-initiated upon subsequent departures of the wavefront from the center of the cylinder until it disappears in the limit of steady state oscillations. We present the solution for this strain field, characterize the nature of this singularity, and discuss its potential role in the mechanical response and evolved morphology of the brain.     

Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs

Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported.     

Molecular architectures for trimetallic d/f/d complexes: magnetic studies of a LnCu2 core

Five new trinuclear Cu-Ln-Cu cluster complexes have been prepared by a one-pot reaction using H3bcn (tris- N,N',N'-(2-hydroxybenzyl)-1,4,7-triazacyclononane) and Ln = La(III), Nd(III), Gd(III), Dy(III), and Yb(III) where the d- and f-block metal ions are in close proximity desirable for magnetic studies. The [LnCu2(bcn)2]ClO4.nH2O complexes possess the same stoichiometry as the previously reported [LnNi2(bcn)2]ClO4.nH2O and [LnZn2(bcn)2]ClO4.nH2O systems. Additionally, the solid state structures of the LnCu2 complexes appear to be isostructural to the LnNi2 and LnZn2 species as determined by their nearly superimposable IR spectra. The similarities in the structures of the [LnTM2(bcn)2]ClO4.nH2O series, where TM = Zn(II), Ni(II), and Cu(II), allow for direct comparison of their magnetic exchange. An empirical approach, removing first-order anisotropic contributions determined from the analogous [LnZn2(bcn)2]ClO4.nH2O was used to study the d/f/d spin interactions in the [LnCu2(bcn)2]ClO4.nH2O complexes. A ferromagnetic exchange was determined where Ln = Gd(III), Dy(III), or Yb(III) and an antiferromagnetic exchange for Ln = Nd(III), identical to the magnetic exchange observed for the [LnNi2(bcn)2]ClO4.nH2O complexes. An exchange integral of 3.67 cm(-1) for the trimetallic [GdCu2(bcn)2]ClO4.3H2O species was determined using a modified spin Hamiltonian. The [Cu(Hbcn)] and the [Cu3(Hbcn)2](ClO4)2 building blocks of the larger coaggregated d/f/d species were also synthesized, and their structures are reported.     

Molecular architectures for trimetallic d/f/d complexes: structural and magnetic properties of a LnNi2 core

A series of cationic, trimetallic d/f/d complexes have been prepared which use a multidentate, macrocyclic amine phenol ligand to coordinate divalent first row d-block transition metal ions (TM) and lanthanides (Ln) ions in close proximity, desirable for magnetic studies. Isolable complexes of the d/f/d cluster compounds with the formula [Ln(TM)2(bcn)2]ClO4.nH2O, where H3bcn is tris-N, N', N'-(2-hydroxybenzyl)-1,4,7-triazacyclononane, TM = Zn(II) and Ni(II) and Ln = La(III), Nd(III), Gd(III), Dy(III), and Yb(III), were synthesized by a one-pot sequential reaction of stoichiometric amounts of H 3bcn with the TM(II) and Ln(III) metal ions. The spontaneously formed cationic complexes were characterized by a variety of analytical techniques including IR, NMR, +ESI-MS, and EA. The [TM(Hbcn)].nH2O and [TM3(bcn)2].nH2O complexes were also synthesized to probe the building blocks of the d/f/d coaggregated species. The solid-state X-ray crystal structures of [GdNi2(bcn)2(CH3CN)2]ClO4.CH3CN and [GdZn2(bcn)2(CH3CN)2]ClO4.CH3CN were determined to be nearly identical with each TM(II) encapsulated in an octahedral geometry by the N3O3 binding pocket of the bcn (3-) ligand. The eight coordinate Gd(III) was bicapped by two [TM(bcn)](-) moieties and coordinated by two solvent molecules. Because of the isostructurality of the [LnZn2(bcn)2]ClO4.nH2O and [LnNi2(bcn)2]ClO4.nH2O complexes, an empirical approach using the LnZn2 magnetic data was utilized to remove first-order anisotropic contributions from the LnNi2 species. Ferromagnetic spin interactions were determined for the [LnNi2(bcn)2]ClO4.nH2O complexes, where Ln = Gd(III), Dy(III), and Yb(III), while an antiferromagnetic exchange was observed for Ln = Nd(III).     

Development of a measuring system for segmented ship models

The use of segmented ship models to test and study various ship responses in model scale poses a challenge to instrumentation and test engineers. In recent years, the authors have developed a segmented ship model to study and trace ice loads acting on the ship hull. The model contains three segments at the bow. Each segment is supported at multiple points which enable the resolution of the location, magnitude, and direction of the external loads. The typical segment support system consists of four vertical, two transverse, and one longitudinal support points with uniaxial compression pression transducers. Stabilization of the segment is achieved by using three specially designed tension links acting in the vertical, transverse and longitudinal directions, respectively. The system is subjected to several levels of calibration which include individual transducer calibration, calibration using internal loading applied by the tension links, external calibration using a specially designed and built calibration rig capable of exerting normal and inclined loads, and calibration of the effects of buoyancy changes in a floating model. The results of calibration and ice-breaking tests indicate that position prediction of the external load can be made within 20 mm. The normal load of less than 100 Newtons can be determined within a few percentage points but the frictional load magnitude and direction are found to be subject to greater errors particularly for low friction factors of the order of 0.1. A.M. Nawwar (SEM Member), presently Associate Professor of Mechanical Engineering, Kuwait University, Kuwait 13060     

Fast,efficient generation of high‐quality atomic charges. AM1‐BCC model: I. Method

The AM1‐BCC method quickly and efficiently generates high‐quality atomic charges for use in condensed‐phase simulations. The underlying features of the electron distribution including formal charge and delocalization are first captured by AM1 atomic charges for the individual molecule. Bond charge corrections (BCCs), which have been parameterized against the HF/6‐31G* electrostatic potential (ESP) of a training set of compounds containing relevant functional groups, are then added using a formalism identical to the consensus BCI (bond charge increment) approach. As a proof of the concept, we fit BCCs simultaneously to 45 compounds including O‐, N‐, and S‐containing functionalities, aromatics, and heteroaromatics, using only 41 BCC parameters. AM1‐BCC yields charge sets of comparable quality to HF/6‐31G* ESP‐derived charges in a fraction of the time while reducing instabilities in the atomic charges compared to direct ESP‐fit methods. We then apply the BCC parameters to a small “test set” consisting of aspirin, d ‐glucose, and eryodictyol; the AM1‐BCC model again provides atomic charges of quality comparable with HF/6‐31G* RESP charges, as judged by an increase of only 0.01 to 0.02 atomic units in the root‐mean‐square (RMS) error in ESP. Based on these encouraging results, we intend to parameterize the AM1‐BCC model to provide a consistent charge model for any organic or biological molecule. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 132–146, 2000