MOESM1 of Accuracy enhancement in the estimation of molecular hydration free energies by implementing the intramolecular hydrogen bond effects

Additional file 1. Contains chemical structures, experimental and calculated solvation free energies of 763 molecules used in this study

Computational Prediction of Molecular Hydration Entropy with Hybrid Scaled Particle Theory and Free-Energy Perturbation Method

Despite the importance of the knowledge of molecular hydration entropy (Δ<i>S</i>_hyd) in chemical and biological processes, the exact calculation of Δ<i><i>S</i></i>_hyd is very difficult, because of the complexity in solute–water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estimating Δ<i><i>S</i></i>_hyd by means of combining the FEP approach and the scaled particle theory (or information theory) to separately calculate the electrostatic solute–water interaction term (Δ<i><i>S</i></i>_elec) and the hydrophobic contribution approximated by the cavity formation entropy (Δ<i><i>S</i></i>_cav), respectively. Decomposition of Δ<i><i>S</i></i>_hyd into Δ<i><i>S</i></i>_cav and Δ<i><i>S</i></i>_elec terms is found to be very effective with a substantial accuracy enhancement in Δ<i><i>S</i></i>_hyd estimation, when compared to the conventional full FEP calculations. Δ<i><i>S</i></i>_cav appears to dominate over Δ<i><i>S</i></i>_elec in magnitude, even in the case of polar solutes, implying that the major contribution to the entropic cost for hydration comes from the formation of a solvent-excluded volume. Our hybrid scaled particle theory and FEP method is thus found to enhance the accuracy of Δ<i><i>S</i></i>_hyd prediction by effectively complementing the conventional full FEP method

Discovery of Low Micromolar Dual Inhibitors for Wild Type and L1196M Mutant of Anaplastic Lymphoma Kinase through Structure-Based Virtual Screening

Although anaplastic lymphoma kinase (ALK) is involved in a variety of malignant human cancers, the emergence of constitutively active mutants with drug resistance has rendered it difficult to identify the new medicines for ALK-dependent cancers. To find the common inhibitors of the wild type ALK and the most abundant drug-resistant mutant (L1196M), we performed molecular docking-based virtual screening of a large chemical library in parallel for the two target proteins. As a consequence of augmenting the accuracy of the docking simulation by implementing a sophisticated hydration free energy term in the scoring function, 12 common inhibitors are discovered with the inhibitory activities ranging from submicromolar to low micromolar levels. The results of the binding free energy decomposition indicate that the biochemical potency of ALK inhibitors can be optimized by reducing the dehydration cost for binding to the receptor protein as well as by strengthening the interactions with amino acid residues in the ATP-binding site. The newly identified ALK inhibitors are found to have a little higher inhibitory activity for the L1196M mutant than for the wild type due to the strengthening of the hydrogen bond interactions in the ATP-binding site. Of the 12 common inhibitors, 2-(5-methyl-benzooxazol-2-ylamino)-quinazolin-4-ol (<b>3</b>) is anticipated to serve as a new molecular scaffold to optimize the biochemical potency because it exhibits low micromolar inhibitory activity with respect to both the wild type and L1196M mutant in spite of the low molecular weight (292.3 amu)

Identification of Novel Inhibitors of Tropomyosin-Related Kinase A through the Structure-Based Virtual Screening with Homology-Modeled Protein Structure

Tropomyosin-related kinase A (TrkA) is a promising target for the development of cancer and pain therapeutics. Here, we report the first successful example of the use of a structure-based virtual screening to identify novel TrkA inhibitors. The accuracy of the virtual screening was improved by introducing an accurate solvation free energy term into the original AutoDock scoring function. We applied a drug design protocol involving homology modeling, docking analysis of a large chemical library, and enzyme inhibition assays to identify six structurally diverse TrkA inhibitors with <i>K</i>_<i>d</i> values ranging from 3 to 40 μM. The significant potencies and good physicochemical properties of these drug candidates strongly support their consideration in a development effort that would involve structure–activity relationship (SAR) studies to optimize the inhibitory activities. We also addressed the structural and energetic features associated with binding of the newly identified inhibitors in the ATP-binding site of TrkA. The results indicate that any structural modifications introduced for the purpose of enhancing the activity of TrkA inhibitors should maximize the attractive interactions within the ATP-binding site and simultaneously minimize the desolvation cost for complexation

Application of Fragment-Based de Novo Design to the Discovery of Selective Picomolar Inhibitors of Glycogen Synthase Kinase‑3 Beta

A systematic fragment-based de novo design procedure was developed and applied to discover new potent and selective inhibitors of glycogen synthase kinase-3 beta (GSK3β). Candidate inhibitors were generated to simultaneously maximize the biochemical potency and the specificity for GSK3β through three design steps: identification of the optimal molecular fragments for the three sub-binding regions, design of proper linking moieties to connect the fragmental building blocks, and final scoring of the generated molecules. By virtue of modifying the ligand hydration free energy term in the scoring function using hybrid scaled particle theory and the extended solvent-contact model, we identified several GSK3β inhibitors with biochemical potencies ranging from low nanomolar to picomolar levels. Among them, the two most potent inhibitors (<b>12</b> and <b>27</b>) are anticipated to serve as promising starting points of drug discovery for various diseases caused by GSK3β because of the high specificity for the inhibition of GSK3β

Computational Design and Discovery of Nanomolar Inhibitors of IκB Kinase β

IκB kinase β (IKKβ) is a useful target for the discovery of new medicines for cancer and inflammatory diseases. In this study, we aimed to identify new classes of potent IKKβ inhibitors based on structure-based virtual screening, <i>de novo</i> design, and chemical synthesis. To increase the probability of finding actual inhibitors, we improved the scoring function for the estimation of the IKKβ-inhibitor binding affinity by introducing proper solvation free energy and conformational destabilization energy terms for putative inhibitors. Using this modified scoring function, we have been able to identify 15 submicromolar-level IKKβ inhibitors that possess the phenyl-(4-phenyl-pyrimidin-2-yl)-amine moiety as the molecular core. Decomposition analysis of the calculated binding free energies showed that a high biochemical potency could be achieved by lowering the desolvation cost and the conformational destabilization for the inhibitor required for binding to IKKβ as well as by strengthening the interactions in the ATP-binding site. The formation of two hydrogen bonds with backbone amide groups of Cys99 in the hinge region was found to be necessary for tight binding of the inhibitors in the ATP-binding site. From molecular dynamics simulations of IKKβ-inhibitor complexes, we also found that complete dynamic stability of the bidentate hydrogen bond with Cys99 was required for low nanomolar-level inhibitory activity. This implies that the scoring function for virtual screening and <i>de novo</i> design would be further optimized by introducing an additional energy term to measure the dynamic stability of the key interactions in enzyme–inhibitor complexes

Discovery of Picomolar ABL Kinase Inhibitors Equipotent for Wild Type and T315I Mutant via Structure-Based de Novo Design

Although the constitutively activated break-point cluster region–Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti-CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of enzyme–inhibitor interaction to enhance the potency of an ABL inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the inhibitors and Met318 should also be considered in designing the potent common inhibitors of the wild-type and T315I mutant of ABL

Systematic Computational Design and Identification of Low Picomolar Inhibitors of Aurora Kinase A

Aurora kinase A (AKA) has served as an effective molecular target for the development of cancer therapeutics. A series of potent AKA inhibitors with the (4-methoxy-pyrimidin-2-yl)-phenyl-amine (MPPA) scaffold are identified using a systematic computer-aided drug design protocol involving structure-based virtual screening, de novo design, and free energy perturbation (FEP) simulations. To enhance the accuracy of the virtual screening to find a proper molecular core and de novo design to optimize biochemical potency, we preliminarily improved the scoring function by implementing a reliable hydration energy term. The overall design strategy proves successful to the extent that some inhibitors reveal exceptionally high potency at low picomolar levels; this was achieved by substituting phenyl, chlorine, and tetrazole moieties on the MPPA scaffold. The establishment of bidentate hydrogen bonds with backbone groups in the hinge region appears to be necessary for the high biochemical potency, consistent with the literature X-ray crystallographic data. The picomolar inhibitory activity also stems from the simultaneous formation of additional hydrogen bonds with the side chains of the hinge region and P-loop residues. The FEP simulation results show that the inhibitory activity surges to the low picomolar level because the interactions in the ATP-binding site of AKA become strong by structural modifications enough to overbalance the increase in dehydration cost. Because of the exceptionally high biochemical potency, the AKA inhibitors reported in this study are anticipated to serve as a new starting point for the discovery of anticancer medicine

The Composite Structure and Two-Peak Emission Behavior of a Ca_1.5Ba_0.5Si₅O₃N₆:Eu²⁺ Phosphor

A Ca_1.5Ba_0.5Si₅O₃N₆:Eu²⁺ phosphor with a monoclinic lattice in the <i>Cm</i> space group exhibiting a composite structure consisting of CaSi₂O₂N₂-like and BaSi₆N₈O-like structures was examined in terms of structure and luminescence. The luminescent properties of the Ca_1.5Ba_0.5Si₅O₃N₆:Eu²⁺ phosphor could be suitable for light-emitting diode applications since it exhibited a promising yellow (or amber) emission peaking at ∼570–590 nm at excitations of 450–460 nm. The present investigation was focused on verifying the composite structure by employing quantum mechanical calculations such as the Hartree–Fock ab initio calculation and a density functional theory calculation along with precise structural and compositional analyses. The two-peak emission behavior ascribed to the composite structure was also examined in terms of continuous wave and time-resolved photoluminescence. In addition, the energy transfer between two activator sites ascribed to the composite structure was examined in detail

Comparison of antigen binding capacities of 297-D4 and 144-A8 antibodies depending on antigen dosage.

<p>Increasing concentrations of GST (A) and GST-BAP31 (B) were coated and incubated with the indicated antibodies. The binding activities of the antibodies are expressed as OD490. Error bars represent standard deviations of the means.</p