D3R Grand Challenge 4: ligand similarity and MM-GBSA-based pose prediction and affinity ranking for BACE-1 inhibitors

The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand Challenge 4 (GC4), which focused on predicting the binding poses and affinity ranking for compounds targeting the $$\beta$$-amyloid precursor protein (BACE-1). Our ligand similarity-based protocol using HYBRID (OpenEye Scientific Software) successfully identified poses close to the native binding mode for most of the ligands with less than 2 Å RMSD accuracy. Furthermore, we compared the performance of our HYBRID-based approach to that of AutoDock Vina and DOCK 6 and found that using a reference ligand to guide the docking process is a better strategy for pose prediction and helped HYBRID to perform better here. We also conducted end-point free energy estimates on molecules dynamics based ensembles of protein-ligand complexes using molecular mechanics combined with generalized Born surface area method (MM-GBSA). We found that the binding affinity ranking based on MM-GBSA scores have poor correlation with the experimental values. Finally, the main lessons from our participation in D3R GC4 are: (i) the generation of the macrocyclic conformers is a key step for successful pose prediction, (ii) the protonation states of the BACE-1 binding site should be treated carefully, (iii) the MM-GBSA method could not discriminate well between different predicted binding poses, and (iv) the MM-GBSA method does not perform well at predicting protein–ligand binding affinities here.     

Box size effects are negligible for solvation free energies of neutral solutes

Hydration free energy calculations in explicit solvent have become an integral part of binding free energy calculations and a valuable test of force fields. Most of these simulations follow the conventional norm of keeping edge length of the periodic solvent box larger than twice the Lennard-Jones (LJ) cutoff distance, with the rationale that this should be sufficient to keep the interactions between copies of the solute to a minimum. However, for charged solutes, hydration free energies can exhibit substantial box size-dependence even at typical box sizes. Here, we examine whether similar size-dependence affects hydration of neutral molecules. Thus, we focused on two strongly polar molecules with large dipole moments, where any size-dependence should be most pronounced, and determined how their hydration free energies vary as a function of simulation box size. In addition to testing a variety of simulation box sizes, we also tested two LJ cut-off distances, 0.65 and 1.0 nm. We show from these simulations that the calculated hydration free energy is independent of the box-size as well as the LJ cut-off distance, suggesting that typical hydration free energy calculations of neutral compounds indeed need not be particularly concerned with finite-size effects as long as standard good practices are followed.     

Missing mass analysis of the A−2 at 6.0 GeV/c

The missing mass spectrum in the region of the A^?₂ has been measured in the reaction π^?p→X^?p at 6.0 GeV/c in the interval 0.27 <|t|<0.42 (GeV/c)², with an optical spark chamber system which simultaneously observed the decay X^?→ηπ^?. A signal of 230 events above background per five MeV interval is observed at the A₂ peak, with a signal-to-background ratio of greater than 1:1. A single D-wave Breit-Wigner distribution with a quadratic background gives a good fit to the data, yielding the parameters M₀=(1.324±0.003) GeV/c² and Γ₀=(0.104±0.009) GeV/c². The spectrum is incompatible with a dipole shape.     

Solitary wave solutions to nonlinear evolution equations in mathematical physics

This paper obtains solitons as well as other solutions to a few nonlinear evolution equations that appear in various areas of mathematical physics. The two analytical integrators that are applied to extract solutions are tan–cot method and functional variable approaches. The soliton solutions can be used in the further study of shallow water waves in (1+1) as well as (2+1) dimensions.     

Physical and chemical evolution of PMDA-ODA during thermal imidization

The processing of poly(imide) films from poly(amic acid) solutions involves the simultaneous loss of solvent and chemical conversion, and may involve structural reorganization such as orientation or crystallization. Here, we describe weight loss, solvent sorption. Fourier transform infrared (FTIR), and wide-angle x-ray scattering (WAXS) studies during thermal imidization of the commercially important poly(imide) PMDA-ODA. The results indicate that imidization proceeds nearly to completion before significant crystallization occurs. The experimental data are interpreted in terms of a triangular phase diagram that makes it possible to plot the processing pathway during the conversion from poly(amic acid) solution to solid poly(imide). In constructing this triangular phase diagram the extent of imidization (i.e., the composition of the poly(amic acid-co-imide) copolymers during conversion) is treated as an independent thermodynamic variable. The form of the triangular phase diagram can be predicted from the Flory-Huggins lattice theory of mixing. There is inevitably a two-phase region present due to the relatively poor solubility of the poly(imide) in the poly(amic acid) solvent (NMP). The specific processing pathway taken depends on the relative amount of solvent loss and imidization during conversion. Further details about the triangular phase diagrams of poly(imides) will require such studies as solvent swelling at intermediate stages of conversion. © 1995 John Wiley & Sons, Inc.     

Peroxycarbenium-mediated C-C bond formation: applications to the synthesis of hydroperoxides and peroxides

The Lewis acid-mediated reaction of alkene nucleophiles with peroxyacetals provides an effective route for the synthesis of homologated peroxides and hydroperoxides. In the presence of Lewis acids such as TiCl(4), SnCl(4), and trimethylsilyl triflate, peroxyacetals and peroxyketals undergo reaction with allyltrimethylsilane, silyl enol ethers, and silyl ketene acetals to afford homoallyl peroxides, 3-peroxyketones, and 3-peroxyalkanoates, respectively. Reactions of peroxyacetals are Lewis acid dependent; TiCl(4) promotes formation of ethers while SnCl(4) and trimethylsilyl triflate promote formation of peroxides. Lewis acid-promoted reactions of silylated hydroperoxyacetals furnish silylated hydroperoxides, which can be deprotected to homologated hydroperoxides. Hydroperoxyketals undergo Lewis acid-mediated allylation to furnish 1,2-dioxolanes via attack of hydroperoxide on the intermediate carbocation. Lewis acid-mediated cyclization of unsaturated peroxyacetals furnishes 1,2-dioxanes, 1,2-dioxepanes, and 1,2-dioxacanes through 6-endo/exo, 7-endo/endo, and 8-endo/endo pathways. The corresponding reactions involving 6-endo/endo and 5-endo/exo pathways were unsuccessful.