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Telomerase is a ribonuceloprotein complex responsible for maintaining telomeres and protecting chromosomal integrity. The human telomerase reverse transcriptase (hTERT) is expressed in ~90% of cancer cells where it confers the capacity for limitless proliferation. Along with its established role in telomere lengthening, telomerase also serves non-canonical extra-telomeric roles in oncogenic signaling, resistance to apoptosis, and enhanced DNA damage response. We report a new class of natural product-inspired covalent inhibitors of telomerase that target the catalytic active site.

MEK4, mitogen-activated protein kinase kinase 4, is overexpressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed. With advances in both computer and biological high-throughput screening, selective chemical entities can be discovered. Structure-based quantitative structure-activity relationship (QSAR) modeling often fails to generate accurate models due to poor alignment of training sets containing highly diverse compounds. Here we describe a highly predictive, nonalignment based robust QSAR model based on a data set of strikingly diverse MEK4 inhibitors. We computed the electrostatic potential (ESP) charges using a density functional theory (DFT) formalism of the donor and acceptor atoms of the ligands and hinge residues. Novel descriptors were then generated from the perturbation of the charge densities of the donor and acceptor atoms and were used to model a diverse set of 84 compounds, from which we built a robust predictive model.

Influenza A virus envelop protein hemagglutinin (HA) plays important roles in viral entry. We previously have reported that MBX2546, a novel influenza A virus inhibitor, binds to HA and inhibits HA-mediated membrane fusion. In this report, we show that (i) both binding and stabilization of HA by MBX2546 are required for the inhibition of viral infection and (ii) the binding of HA by MBX2546 represses the low-pH-induced conformational change in the HA, which is a prerequisite for membrane fusion. Mutations in MBX2546-resistant influenza A/PR/8/34 (H1N1) viruses are mapped in the HA stem region near the amino terminus of HA2. Finally, we have modeled the binding site of MBX2546 using molecular dynamics and find that the resulting structure is in good agreement with our results. Together, these studies underscore the importance of the HA stem loop region as a potential target for therapeutic intervention.

The viral envelope protein hemagglutinin (HA) plays a critical role in influenza entry and thus is an attractive target for novel therapeutics. The small molecule tert-butylhydroquinone (TBHQ) has previously been shown to bind to HA and inhibit HA-mediated entry with low micromolar potency. However, enthusiasm for the use of TBHQ has diminished due to the compound's antioxidant properties. In this work we show that the antioxidant properties of TBHQ are not responsible for the inhibition of HA-mediated entry. In addition, we have performed a structure-activity relationship (SAR) analysis of TBHQ derivatives. We find that the most promising compound, 3-Tert-butyl-4-methoxyphenol, exhibits enhanced potency (IC50 = 0.6 μM), decreased toxicity (CC50 = 340 μM), and increased stability (t1/2 < 48 h). Finally, we have characterized the binding properties of 3-Tert-butyl-4-methoxyphenol using NMR and molecular dynamics to guide future efforts for chemical optimization.

Studies reported here are aimed to investigate the important structural features that characterize the human EP(3) antagonists. Based on the knowledge of low-energy conformation of the endogenous ligand, the initial hit analogs were prepared. Subsequently, a ligand-based lead optimization approach using pharmacophore model generation was utilized. A 5-point pharmacophore using a training set of 19 compounds spanning the IC(50) data over 4-log order was constructed using the HypoGen module of Catalyst. Following pharmacophore customization, using a linear structure-activity regression equation, a six feature three-dimensional predictive pharmacophore model, P6, was built, which resulted in improved predictive power. The P6 model was validated using a test set of 11 compounds providing a correlation coefficient (R(2)) of 0.90 for predictive versus experimental EP(3) IC(50) values. This pharmacophore model has been expanded to include diverse chemotypes, and the predictive ability of the customized pharmacophore has been tested.

The EP3 receptor on the platelet mediates prostaglandin E2 potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP3 receptor antagonists. A simultaneous chemical optimization and druglike assessment of prioritized molecules converged on a lead compound 50 (DG-041) that displayed favorable in vitro and functional activities as an inhibitor of human platelet aggregation. This agent is currently in human clinical trials for the treatment of atherothrombosis.

Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (30 mg/mL) and high oral bioavailability (80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.

We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein-protein interaction surfaces for fragment binding. We screened the FOL library against leukotriene A4 hydrolase (LTA4H) by X-ray crystallography. A diverse set of fragments including derivatives of resveratrol, nicotinamide, and indole were identified as efficient ligands for LTA4H. These fragments were elaborated in a small number of synthetic cycles into potent inhibitors of LTA4H representing multiple novel chemotypes for modulating leukotriene biosynthesis. Analysis of the fragment-bound structures also showed that the fragments comprehensively recapitulated key chemical features and binding modes of several reported LTA4H inhibitors.

A graph theoretically formulated circumscribing algorithm for the fullerene growth mechanism has been analyzed using the quantum chemical AM1 method. Following different routes, two small fullerenes C28 (Td and D2) and C26 (D3h) have been constructed from monocyclic/polycyclic precursors and circumscribed with appropriate carbon belts. The deformation energies (DE) and the average bond lengths 〈R〉 of the precursors have been computed. The DE values suggest that there is a chance of bond cleavage of the polycyclic precursors as the growth process proceeds toward the cage formation. On the other hand, the monocyclic precursors are found to have significantly lower deformation energies than the polycyclic precursors. Further, with analysis of 〈R〉 values of the polycyclic and monocyclic cases at different stages, it is observed that the 〈R〉 values of the polycyclic cases decrease gradually, depicting a shrinkage in the precursors which may be detrimental to the growth process, whereas monocyclic precursors te...

Insertion of a C2 molecule (fragment) into the cavity of a hexagonal belt containing 10 hexagons generates a honeycomb lattice (C42H16) and two hydrocarbons containing one and two pairs of {7,5} ring pairs. The vibrational frequency analysis reveals that the hydrocarbon having only one {7,5} ring pair behaves as a transition-state-like structure. The generation of the hydrocarbon containing two {7,5} ring pairs appears to be an innate process compared with the honeycomb lattice when the C2 fragment is inserted into the vacant space of the hexagonal belt. A very small amount of excitation energy (0.0108 kcal/mol) is required for the annihilation of a {7,5} ring pair to a {6,5} ring pair. Considering two common frames, the motion of the {7,5} and {6,5} ring pairs are studied. The motion of these ring pairs are found to be so natural that there is an insignificant change in the property-like second-order hyperpolarizability (〈γ〉).

The perfect matching (Kekule structure count) of certain polycyclic aromatic hydrocarbons (benzenoids, i.e., PAH6) having mirror plane symmetry is obtained through a computer program. A computer operation in the form of an initial approximation (P, Q) is selected such that it extracts the quadratic factors (QFs) like (X2 − AiX + Bi) and linear factors (LFs) like (X − ai) from the characteristic polynomials (CPs) of the different components obtained from the mirror plane fragmentation technique following an energy scale. The most minimum energy factor is extracted first, and then the next higher factor is extracted. This process of gradual extraction of the energy factor concludes after the HOMO level of the fragment is extracted. These factors contain the positive Huckel eigenvalues which are responsible for the Kekule structure count and the π-electron energy (Eπ) of the benzenoid molecules. Ai, Bi, and ai are used to correlate (Eπ)i and Ki of the fragments. A linear relationship between the total π-elec...

The net effect of a heteroatomic center (combined effect of h and k Huckel parameters) on the eigenvalues of certain heteroconjugated molecules is examined. The role of the k parameter is judged by comparing the eigenvalues of the vertex-weighted (self-loop) graphs with those of the vertex-edge-weighted graphs. The pairing of the eigenvalues for the above class of molecules is observed by using the original pairing theorem (Coulson, C. A.; Rushbrooke, G. S. Proc. Cambridge Philos. Soc. 1940, 36, 193−200. Coulson, C. A.; Leary, B. O.; Mallion, R. B. Huckel Theory for Organic Chemists; Academic Press: London, 1978; pp 90−110), the restricted extension form of it (Mallion, R. B.; Schwenk, A. J.; Trinajstic, N. In Recent Advances in Graph Theory; Fiedler, M., Ed.; Academia: Prague, 1975; p 345. Trinajstic, N. Croat. Chem. Acta 1977, 49 (4), 593−633), and a different pairing scheme proposed in this work. The newly proposed scheme for pairing of the eigenvalues for a monocyclic heteroconjugated system contain...

Page 4702. In Figure 2, the chemical structure of compound 19 (DG-051) was incorrectly drawn as the (R)-enantiomer. Compound 19 is the (S)-enantiomer and is properly shown in the three-dimensional crystal structure image at the right-hand side in the corrected figure below. Figure 2 Panels showing ligand binding to LTA4H for compounds described in the manuscript. Enzyme assay IC50 values are in μM, human whole blood cell assay IC50 values are in nM when reported, and ligand efficiency (LE) values are in kcal/(mol·heavy atom). Compound structures are displayed as yellow stick structures, and LTA4H is displayed in gray. Green mesh corresponds to the Fo − Fc (difference) electron density at the 3.0σ level of the crystal structure with the compound omitted from the model. Polar contacts with LTA4H and/or bound water molecules are shown as red dashed lines. PDB IDs for each structure are indicated. On page 4704, right hand column, first paragraph, line 19 and second paragraph line 22, (R)-prolinol should be changed to (S)-prolinol. Supporting Information Page S16. In Table 2, the chemical structure of compound 19 (DG-051) was incorrectly drawn as the (R)-enantiomer. The correct (S)-enantiomer has been included in the revised version of Supplemental Table 2 below. Supplemental Table 2. Comparative IC50 data for peptidase, hydrolase, and HWB assays. View it in a separate window Supplemental Table 2. Comparative IC50data for peptidase, hydrolase, and HWB assays. For all compound structures described in this work, inhibition assays were carried out using at least two independent methods, either the hydrolase assay, peptidase assay and/or a hydrolase assay in human whole blood. See Materials and Methods section for details. All results are given as IC50 values in μM, with the number of replicates and the standard error of the mean indicated where applicable.