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The structure-based optimization of a series of estrogen receptor-beta (ERbeta) selective ligands is presented. Using ab initio quantum mechanics, it is demonstrated that certain functional groups incorporated during lead optimization are able to experience a differential interaction with ERalpha Met(sub 421) relative to ERbeta IIe(sub 373) based on both electrostatic and dispersive effects.

Using a density matrix formalism we derive a general expression for the resonant response of an ensemble of molecular aggregates to two optical pulses. The aggregates, which can be of arbitrary geometry, are described by a Frenkel exciton Hamiltonian including exciton–exciton interactions. A hierarchy of resonant coherent transient signals is generated having wave vectors sk1+(1-s)k2, where ki is the wave vector of the ith pulse and s is an integer. General expressions for the differential pump–probe absorption spectrum D(ω;tD) (s=0) and the photon echo Iecho(tD) (s=-1) are presented for arbitrary pulse intensities. Applications are made to a linear chain of interacting Frenkel excitons with nearest neighbor exciton–exciton interaction A and exciton transfer J. Analytical expressions for D(ω;tD) and Iecho(tD) are obtained which are valid to third order in the aggregate-field interaction. The influence of the optically active red (blue) biexciton which detaches from the bottom (top) of the two-exciton band when A<-2|J| (A>=2|J|) is investigated. Biexcitons appear as extra peaks in D(ω;tD) and as oscillations in Iecho(tD). Finite size effects are responsible for quantum beat oscillations in D(ω;tD) and long time oscillations in the echo decay. Quantum beats arise predominantly from the difference between the lowest one-exciton frequencies. Our theory successfully describes the salient spectral features in the pump–probe spectra of J-aggregates. © 1995 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Examines the absorption and spontaneous emission in aggregates of conjugated polymers. Relationship between the radiative decay rate of exciton and the number of polymers; Effects of intermolecular interactions on exciton sizes and energies; Implication of J-aggregate formation for the absorption and emission of polymer aggregates.

Studies spontaneous emission and absorption in an aggregate of pi-conjugated oligomers. Aggregate Hamiltonian; Aggregate-field interaction Hamiltonian; Evaluation of absorption spectra for aggregates; Radiative emission; Radiative decay in an isolated oligomer; Radiative decay in aggregates.

Studies the effects of intermacrocycle interactions on the second hyperpolaribilities of cofacial phthalocyanine dimers and trimers. Presentation of theoretical analysis based on the Frenkel exciton model for a chain of three level molecules; Identification of two mechanisms which lead to enhancements in the dimer and trimer value; Description of the first mechanism.

Low-temperature UV-vis absorption and Stark-effect hole-burning spectra of Zn substituted cytochrome c are studied experimentally and theoretically using quantum mechanical and Poisson-Boltzmann electrostatics models. It is demonstrated that the magnitude of the low-temperature Q(0,0) band splitting observed in Zn substituted cyt c from horse heart, tuna heart, and yeast follows the same trend as in the native Fe(II) proteins.

Proper accounting of the positional/orientational/conformational entropy loss associated with protein-ligand binding is important to obtain reliable predictions of binding affinity. Herein, we critically examine two simplified statistical mechanics-based approaches, namely a constant penalty per rotor method, and a more rigorous method, referred to here as the partition function-based scoring (PFS) method, to account for such entropy losses in high-throughput docking calculations. Our results on the estrogen receptor β and dihydrofolate reductase proteins demonstrate that, while the constant penalty method over-penalizes molecules for their conformational flexibility, the PFS method behaves in a more 'ΔG-like' manner by penalizing different rotors differently depending on their residual entropy in the bound state. Furthermore, in contrast to no entropic penalty or the constant penalty approximation, the PFS method does not exhibit any bias towards either rigid or flexible molecules in the hit list. Preliminary enrichment studies using a lead-like random molecular database suggest that an accurate representation of the 'true' energy landscape of the protein-ligand complex is critical for reliable predictions of relative binding affinities by the PFS method. Proteins 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We present the structure-based optimization of a series of estrogen receptor-β (ERβ) selective ligands. X-ray cocrystal structures of these ligands complexed to both ERα and ERβ are described. We also discuss how molecular modeling was used to take advantage of subtle differences between the two binding cavities in order to optimize selectivity for ERβ over ERα. Quantum chemical calculations are utilized to gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservative residue substitutions in the ligand binding pocket, the most selective compounds have greater than 100-fold selectivity for ERβ relative to ERα when measured using a competitive radioligand binding assay. [ABSTRACT FROM AUTHOR]

Presents evidence for hydrogen bonding between helices and water based on infrared spectra of amide groups in alpha-helical polypeptides. Sensitivity of infrared spectral frequencies to secondary structure; Distinction between solvent-exposed and buried amide groups through spectral shifts; Temperature- and bond strength-dependence of the shifts.

Abstract: The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT2A receptor antagonists, is described. The synthesis and structure–activity relationship (SAR) of this novel series of compounds is also presented. [Copyright &y& Elsevier]

The synthesis and structure–activity relationships of a series of simple biphenyls is described. Optimization of the 4-hydroxy-biphenyl template led to compounds with ERβ selectivity on the order of 20–70-fold. [Copyright &y& Elsevier]

Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile. [ABSTRACT FROM AUTHOR]

Abstract: Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE-1) and γ-secretase leads to formation of β-amyloid (Aβ) a key component of amyloid plaques, which are considered the hallmark of Alzheimer’s disease. Small molecule inhibitors of BACE-1 may reduce levels of Aβ and thus have therapeutic potential for treating Alzheimer’s disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S1 and S2′ pockets leading to submicromolar BACE-1 inhibitors. [Copyright &y& Elsevier]

Relative binding affinity prediction is a critical component in computer aided drug design. A significant amount of effort has been dedicated to developing rapid and reliable in silico methods. However, robust assessment of their performance is still a complicated issue, as it requires a performance measure applicable in the prospective setting and more importantly a true null model that defines the expected performance of being random in an objective manner. Although many performance metrics, such as the Pearson correlation coefficient ( r ), mean unsigned error (MUE), and root-mean-square error (RMSE), are frequently used in the literature, a true and nontrivial null model has yet been identified. To address this problem, here we introduce an interval estimate as an additional measure, namely, the prediction interval (PI), which can be estimated from the error distribution of the predictions. The benefits of using the interval estimate are (1) it provides the uncertainty range in the predicted activities, which is important in prospective applications, and (2) a true null model with well-defined PI can be established. We provide one such example termed the Gaussian Random Affinity Model (GRAM), which is based on the empirical observation that the affinity change in a typical lead optimization effort has the tendency to distribute normally N (0, σ). Having an analytically defined PI that only depends on the variation in the activities, GRAM should, in principle, allow us to compare the performance of relative binding affinity prediction methods in a standard way, ultimately critical to measuring the progress made in algorithm development.

Over the last decade, a number of computational methods have been developed, which attempt to evaluate the thermodynamic properties of individual water molecules at the solute-solvent interface, in order to assess contributions to protein-ligand binding. In some cases, these tools tell us what we already know, e.g. that hydrophobic pockets prefer lipophilic substituents, and in other cases the methods only seem to add clarity when retrospectively applied. Hence we have grappled with how to utilize such approaches to understand non-intuitive results and to generate chemistry ideas that otherwise would not have been developed. Here we provide our perspective on these methods and describe how results have been interpreted and applied. We include examples from GSK and elsewhere that highlight how water methods have been (1) utilized retrospectively to explain non-intuitive structure- activity relationships and (2) applied prospectively for chemistry design. Finally, we discuss where this field of study could lead to maximal impact in drug discovery research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Lp-PLA 2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA 2 . The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC 50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA 2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA 2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

A method that identifies the hydration shell structure of proteins and estimates the relative free energies of water molecules within that hydration shell is described. The method, which we call "SPAM" (maps spelled in reverse), utilizes explicit solvent molecular dynamics (MD) simulations to capture discrete hydration sites at the water-protein interface and computes a local free energy measure from the distribution of interaction energies between water and the environment at a specific site. SPAM is able to provide a qualitative estimate of the thermodynamic profile of bound water molecules that correlates nicely with well-studied structure-activity relationships and observed binding "hot spots". This is demonstrated in retrospective analyses of HIV1 protease and hen egg white lysozyme, where the effects of water displacement and solvent binding have been studied extensively. The simplicity and effectiveness of SPAM allow for prospective application during the drug discovery process.

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).

The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERbeta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERbeta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.

New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.