Solid-phase synthesis of an arylsulfone hydroxamate library

Synthesis of an arylsulfone hydroxamate lead optimization library is presented. Biological activity of representative examples is given to demonstrate the value of this approach for lead optimization.     

Computer-aided drug design: getting the best results.

There are two major stages in the design of drug molecules: lead-molecule development and lead-molecule optimization. Whereas a variety of computational chemistry and molecular modeling (CC/MM) techniques are now routinely and successfully applied to the optimization stage of drug design, the generation of initial lead compounds has proven a more difficult problem for the CC/MM approach. Only recently has the design of lead molecules by this route become a subject of active research. This article looks at the factors which must be considered carefully when incorporating CC/MM methods into different aspects of drug-design strategies.     

Theoretical analysis of two ACO approaches for the traveling salesman problem

Bioinspired algorithms, such as evolutionary algorithms and ant colony optimization, are widely used for different combinatorial optimization problems. These algorithms rely heavily on the use of randomness and are hard to understand from a theoretical point of view. This paper contributes to the theoretical analysis of ant colony optimization and studies this type of algorithm on one of the most prominent combinatorial optimization problems, namely the traveling salesperson problem (TSP). We present a new construction graph and show that it has a stronger local property than one commonly used for constructing solutions of the TSP. The rigorous runtime analysis for two ant colony optimization algorithms, based on these two construction procedures, shows that they lead to good approximation in expected polynomial time on random instances. Furthermore, we point out in which situations our algorithms get trapped in local optima and show where the use of the right amount of heuristic information is provably beneficial.     

Amino acid supplementation enhances urokinase production by HT-1080 cells

Medium optimization is an important strategy that can lead to several fold increase in the production of proteins in cell culture. However, the usual methods of medium optimization are complex and time consuming. Urokinase is a widely employed thrombolytic drug for the treatment of stroke. We describe here medium optimization for maximizing urokinase production by HT-1080 cells using supplementation of specific amino acids. The new specifically designed method resulted in 240 % increase in urokinase productivity.     

Improving the SNR of EEG generated by deep sources with weighted multielectrode leads

We have developed a multielectrode lead technique to improve the signal-to-noise ratio (SNR) of scalp-recorded electroencephalography (EEG) signals generated deep in the brain. The basis of the method lies in optimization of the measurement sensitivity distribution of the multielectrode lead. We claim that two factors improve the SNR in a multielectrode lead: (1) the sensitivity distribution of a multielectrode lead is more specific in measuring signals generated deep in the brain and (2) spatial averaging of noise occurs when several electrodes are applied in the synthesis of a multielectrode lead. We showed theoretically that within a three-layer spherical head model the sensitivity distributions of multielectrode leads are more specific for deep sources than those of traditional bipolar leads. We also estimated with simulations and with preliminary measurements the total improvement in SNR achieved by both the more specific lead field and spatial averaging. Results obtained with simulations and with experimental measurements show an apparent improvement in SNR obtained with multielectrode leads. This encourages for future development of the method.     

Utilization of fluorescence polarization and time resolved fluorescence resonance energy transfer assay formats for SAR studies: Src kinase as a model system

High-throughput screening (HTS), a major component of lead identification, often utilizes fluorescence-based assay technologies. For example, HTS kinase assays are formatted using a variety of fluorescence-based assay technologies including, but not limited to, dissociation enhanced lanthanide fluoroimmunoassay (DELFIA), time-resolved fluorescence resonance energy transfer (TR-FRET), and fluorescence polarization (FP). These assays offer tremendous advantages such as a nonradioactive format, ease of automation, and excellent reproducibility. Fluorescence-based assays frequently used for lead identification can also be useful for structure activity relationship (SAR) studies during lead optimization. An important issue when assessing an assay to be used for SAR is the ability of the assay to discriminate high-affinity small molecule inhibitors (pM-nM) from low-affinity inhibitors (microM-mM). The purpose of this study was to utilize HTS-friendly assay formats for SAR by developing TR-FRET, FP, and DELFIAassays measuring Src kinase activity and to define the theoretical lower limit of small molecule inhibitor detection achievable with these assay formats. The authors show that 2 homogeneous assay formats, TR-FRET and FP, allowed for the development of Src kinase assays with a lower limit of detection of K(i) = 0.01 nM. This study indicates that assay technologies typically used for HTS can be used during lead optimization by providing quantitative measurements of compound activity critical to driving SAR studies.     

Examination of the computed molecular properties of compounds selected for clinical development

We have conducted a systematic evaluation of the calculated molecular properties of compounds in clinical development and have found that the development process selects for compounds that have certain computed physical properties. In particular, as the stage of development progresses, compounds that are advanced have lower calculated octanollwater partition coefficient (ClogP), polar surface area, and molecular weight. The findings of this study provide guidance for combinatorial library design and lead selection, which may enhance the chance for ultimate success in lead optimization.     

Simultaneous determination of lot size and production rate at capacity-constrained multiple-product systems

In the capacity constrained manufacturing systems where multiple product types are manufactured, the products are often produced in lots. Although the lot production may increase the system throughput by reducing changeover times, it may also increase production lead time because each item in a large lot has a long waiting time. Hence, a production manager should consider both throughput and lead time at the same time when deciding production lot sizes. This paper, which is an extension to the previous work done in Koo et al. (2007) that assumes homogeneous setup times, addresses a lot sizing problem in the system with multiple product types and unequal setup times. We develop a non-linear optimization model for simultaneous determination of throughput rate and lot size for each product. Since this optimization model cannot be solved analytically, we propose a heuristic solution procedure by analyzing the characteristics of the problem. Some numerical examples are presented to validate the proposed model, and finally the performance of the heuristic procedure is evaluated by comparison with the results of simulation experiments.     

Discovery of novel and potent CRTH2 antagonists

High throughput screening of our chemical library for CRTH2 antagonists provided a lead compound 1a. Initial optimization of the lead led to the discovery of a novel, potent and orally bioavailable CRTH2 antagonist 17.     

Identification of second-generation P2X3 antagonists for treatment of pain

A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.     

Recent Results in the Search for New Molecules with Ambergris Odor

The synthesis of new odorant molecules is still a challenging task for the fragrance chemist, because now as ever it is difficult to predict the odor properties of small organic molecules. Therefore, certain tools, such as, e.g., lead‐structure optimization of existing odorants, are helpful techniques. In this article, we describe the synthesis and the odor properties of a new molecule derived by the so‐called ‘seco’ lead‐structure optimization of the ambergris compound Ambroxide^®. Based on these results, more representatives with similar structures have been synthesized and evaluated for their olfactory properties.     

Barstar is electrostatically optimized for tight binding to barnase

We used a novel charge optimization technique to study the small ribonuclease barnase and to analyze its interaction with a natural tight binding inhibitor, the protein barstar. The approach uses a continuum model to explicitly determine the charge distributions that lead to the most favorable electrostatic contribution to binding when competing desolvation and interaction effects are included. Given its backbone fold, barstar is electrostatically optimized for tight binding to barnase when compared with mutants where residues have been substituted with one of the 20 common amino acids. Natural proteins thus appear to use optimization of electrostatic interactions as one strategy for achieving tight binding.     

On stiffness of scaffolds for bone tissue engineering—a numerical study

Tissue scaffolds are typically designed and fabricated to match native bone properties. However, it is unclear if this would lead to the best tissue ingrowth outcome within the scaffold as neo-tissue keeps changing the stiffness of entire construct. This paper presents a numerical method to address this issue for design optimization and assessment of tissue scaffolds. The elasticity tensors of two different types of bones are weighted by different multipliers before being used as the targets in scaffold design. A cost function regarding the difference between the effective elasticity tensor, calculated by the homogenization technique, and the target tensor, is minimized by using topology optimization procedure. It is found that different stiffnesses can lead to different remodeling results. The comparison confirms that bone remodeling is at its best when the scaffold elastic tensor matches or is slightly higher than the elastic properties of the host bone.     

Optimization of the electrostatic interactions in proteins of different functional and folding type

The 3-dimensional optimization of the electrostatic interactions between the charged amino acid residues was studied by Monte Carlo simulations on an extended representative set of 141 protein structures with known atomic coordinates. The proteins were classified by different functional and structural criteria, and the optimization of the electrostatic interactions was analyzed. The optimization parameters were obtained by comparison of the contribution of charge-charge interactions to the free energy of the native protein structures and for a large number of randomly distributed charge constellations obtained by the Monte Carlo technique. On the basis of the results obtained, one can conclude that the charge-charge interactions are better optimized in the enzymes than in the proteins without enzymatic functions. Proteins that belong to the mixed αβ folding type are electrostatically better optimized than pure α-helical or β-strand structures. Proteins that are stabilized by disulfide bonds show a lower degree of electrostatic optimization. The electrostatic interactions in a native protein are effectively optimized by rejection of the conformers that lead to repulsive charge-charge interactions. Particularly, the rejection of the repulsive contacts seems to be a major goal in the protein folding process. The dependence of the optimization parameters on the choice of the potential function was tested. The majority of the potential functions gave practically identical results.     

Discovering novel ligands for macromolecules using X-ray crystallographic screening

The need to decrease the time scale for clinical compound discovery has led to innovations at several stages in the process, including genomics/proteomics for target identification, ultrahigh-throughput screening for lead identification, and structure-based drug design and combinatorial chemistry for lead optimization. A critical juncture in the process is the identification of a proper lead compound, because a poor choice may generate costly difficulties at later stages. Lead compounds are commonly identified from high-throughput screens of large compound libraries, derived from known substrates/inhibitors, or identified in computational prescreeusing X-ray crystal structures. Structural information is often consulted to efficiently optimize leads, but under the current paradigm, such data require preidentification and confirmation of compound binding. Here, we describe a new X-ray crystallography-driven screening technique that combines the steps of lead identification, structural assessment, and optimization. The method is rapid, efficient, and high-throughput, and it results in detailed crystallographic structure information. The utility of the method is demonstrated in the discovery and optimization of a new orally available class of urokinase inhibitors for the treatment of cancer.     

Methods of ambulatory detection and treatment of cardiac arrhythmias using implantable cardioverter-defibrillators

The use of the implantable cardioverter-defibrillator (ICD) for the treatment of ventricular fibrillation, a condition that can lead to sudden cardiac death, is examined. Topics relevant to the development and implementation of ICD technology, such as defibrillation threshold optimization, battery design, lead configuration, arrhythmia-detection algorithms, and pacemakers-ICD interactions, are described. Clinical situations involving the surgical implantation procedures and the quality of life after implantation are also considered. Cost-benefit analysis of ICD treatment as well as an overview of cardiac arrhythmias and emerging technologies are also included. A survey of ICD recipients was conducted and its results are discussed.     

Discovery and lead identification of quinazoline-based BRD4 inhibitors

A new series of quinazoline-based analogs as potent bromodomain-containing protein 4 (BRD4) inhibitors is described. The structure-activity relationships on 2- and 4-position of quinazoline ring, and the substitution at 6-position that mimic the acetylated lysine are discussed. A co-crystallized structure of 48 (CN750) with BRD4 (BD1) including key inhibitor-protein interactions is also highlighted. Together with preliminary rodent pharmacokinetic results, a new lead (65, CN427) is identified which is suitable for further lead optimization.     

Comments on optimization of glycolysis

A recently proposed function for optimization of anaerobic glycolysis is analysed. The maximum value of this optimization function is shown in general to lead to a conserved energy yield of 50% for any coupled reaction. Maximization of the optimization function is shown to correspond to maximizing the product of two variables, the sum of which is constant. The maximum value of the product is always obtained when the two variables have the same size.     

Functional assays as prismatic views of drug activity: relevance to new drug discovery

The two main processes involved in new drug discovery are screening and lead optimization; the latter process encompasses the dialogue between pharmacologists and medicinal chemists with the aim of maximizing primary activity and druglike properties of compounds. The pharmacological assay is the main tool in both of these processes; this will be discussed with special attention to new information regarding the signaling and networking of seven transmembrane receptors. In particular, the assays used for lead optimization will be discussed in terms of detecting and developing drugs that specifically emphasize some signaling pathways and not others, all through the stabilization of unique receptor protein conformations. There is considerable data to indicate that these are real phenomena that may be exploited for therapeutic advantage. A therapeutically relevant example will be discussed from a recent program designed to block entry of HIV-1 for the prevention and therapy of AIDS. The allosteric modulator aplaviroc (873140) and other allosteric modulators will be highlighted with reference to the development of future drugs that block the involvement of receptors in pathological process but otherwise allow them to function normally. In AIDS, this would allow the natural chemokine systems to assist in the protection against further HIV-1 infection.     

Functional Assays as Prismatic Views of Drug Activity: Relevance to New Drug Discovery

The two main processes involved in new drug discovery are screening and lead optimization; the latter process encompasses the dialogue between pharmacologists and medicinal chemists with the aim of maximizing primary activity and druglike properties of compounds. The pharmacological assay is the main tool in both of these processes; this will be discussed with special attention to new information regarding the signaling and networking of seven transmembrane receptors. In particular, the assays used for lead optimization will be discussed in terms of detecting and developing drugs that specifically emphasize some signaling pathways and not others, all through the stabilization of unique receptor protein conformations. There is considerable data to indicate that these are real phenomena that may be exploited for therapeutic advantage. A therapeutically relevant example will be discussed from a recent program designed to block entry of HIV-1 for the prevention and therapy of AIDS. The allosteric modulator aplaviroc (873140) and other allosteric modulators will be highlighted with reference to the development of future drugs that block the involvement of receptors in pathological process but otherwise allow them to function normally. In AIDS, this would allow the natural chemokine systems to assist in the protection against further HIV-1 infection.