Combinatorial Chemistry & High
Throughput Screening, Vol. 6, No. 1, 2003
Contents
Developing
the Molecular Modelling of Diffusion in Zeolites as a High Throughput Catalyst
Screening Technique Pp.1-9
Ramesh Ch. Deka and Rajappan Vetrivel
Purification
Strategies for Combinatorial and Parallel Chemistry Pp.11-27
Paul
J. Edwards
Use
of Intein-Directed Peptide Biosynthesis to Improve Serum Stability and
Bioactivity of a Gelatinase Inhibitory Peptide Pp.29-35
Mikael
Björklund, Heli Valtanen, Harri Savilahti and Erkki Koivunen
DBU-Assisted
Cyclorelease Elimination: Combinatorial Synthesis and g- Glutamyl Cysteine Synthetase and Glutathione-S-Transeferase
Modulatory Effect of C-Nucleoside Analogs Pp.37-50
R.C.
Mishra, Neetu Tewari, Kavita Arora, Rumana Ahmad, R.P. Tripathi, V.K. Tiwari,
R.D. Walter and A.K. Srivastava
Lead
Generation – Enhancing the Success of Drug Discovery by Investing in the Hit to
Lead Process Pp.51-66
Alexander
Alanin, Matthias Nettekoven, Edward Roberts and Andrew W. Thomas
Design
and Peptide-Based Validation of Phage Display Antibodies for Proteomic Biochips
Pp.67-78
N.
Stich, G. van Steen and T. Schalkhammer
Solid-Phase
Synthesis of Heterocyclic Aromates: Applicability towards Combinatorial
Chemistry; a Review Pp.79-99
E.
Gelens, W.J. Koot, W.M.P.B. Menge, H.C.J. Ottenheijm and H. Timmerman
Abstracts
[Back to top] Developing
the Molecular Modelling of Diffusion in Zeolites as a High Throughput Catalyst Screening
Technique
Ramesh
Ch. Deka and Rajappan Vetrivel
Molecular modelling techniques have been used to screen zeolite catalysts for their suitability for organic synthesis. For example, we have used these techniques to study the alkylation of aromatic molecules which are important in the fine-chemical and drug industries. A survey of all such efforts is reviewed in this article. The application of molecular modelling techniques in a systematic manner is an efficient first step in the design of zeolite catalysts. As a qualitative screening tool, molecular graphics is used to visualize how well the reactant and product molecules fit inside the pores of the zeolites. Using a hybrid of several molecular modelling methods, which combines molecular dynamics (MD) and Monte Carlo methods with energy minimization, it is possible to determine the minimum energy locations of the molecules inside the zeolites cages. The minimum energy configurations determined by this hybrid method are taken as a starting point for diffusion of the molecules through the zeolite channels. When a molecule is allowed to diffuse through zeolite channel, the molecule attains some maxima and minima in its diffusion energy profile. From the differences between a maximum and a minimum energy configuration, the diffusion energy barrier for the molecule can be calculated in the zeolites. By comparing the diffusion energy barriers for various isomers of a molecule in different zeolites, it is possible to find out the most suitable zeolite for achieving the required shape-selectivity. In addition, factors influencing the diffusivity of the molecules and consequently the shape selectivity are derived. The list of factors and their relative importance are analysed to derive valuable guidelines to design shape selective zeolite catalysts for a given reaction. Thus, the ultimate aim of these studies is to develop a high throughput computational screening process for the selection of shape-selective zeolite catalysts for various reactions.
The dynamic behaviour of molecules inside the pores of zeolites can be studied using MD methods. Since MD is computationally time consuming, it is more efficient to screen the possible zeolite catalysts by energy minimization methods and then perform MD in specific zeolites. More accurate values of diffusivity of the molecules can be calculated using MD methods, and these values can be correlated with the shape-selectivity observed experimentally and /or derived from diffusion energy barrier calculations.
[Back to top] Purification Strategies for
Combinatorial and Parallel Chemistry
Paul
J. Edwards
This review surveys the methods developed for the purification of intermediates and final compounds originating from parallel and combinatorial chemistry. Included will be reviews of polymerassisted purification, liquid-phase combinatorial chemistry, fluorous synthesis, liquid-liquid and solid-phase extraction, reverse-phase HPLC and supercritical fluid chromatography. A critique of each method is given, highlighting the methodologies strengths and weaknesses.
[Back to top] Use of
Intein-Directed Peptide Biosynthesis to Improve Serum Stability and Bioactivity
of a Gelatinase Inhibitory Peptide
Mikael
Björklund, Heli Valtanen, Harri Savilahti and Erkki Koivunen
Screening of phage display libraries allows rapid identification of peptides binding to a target. However, functional analysis of the phage sequences and their reproduction as soluble and stable peptides are often the most time-consuming part in the screening. We have used here intein-based peptide biosynthesis to produce a phage-display derived gelatinase inhibitory peptide CTTHWGFTLC and to identify the critical residues for gelatinase inhibitory activity by performing alanine-scanning mutagenesis. By biosynthetic incorporation of 5-fluorotryptophan, we obtained an inhibitor of MMP-2 and MMP-9 gelatinases that showed a 6-fold enhancement in serum stability in comparison to the wild-type peptide. The new peptide also had an improved ability to inhibit tumor cell migration. These studies indicate the utility of intein methodology for synthesis and design of peptides obtained by phage display.
[Back to top] DBU-Assisted Cyclorelease Elimination: Combinatorial Synthesis and g- Glutamyl Cysteine Synthetase and
Glutathione-S-Transeferase Modulatory Effect of C-Nucleoside Analogs
R.C. Mishra, Neetu Tewari, Kavita Arora, Rumana Ahmad, R.P. Tripathi, V.K. Tiwari, R.D. Walter and A.K. Srivastava
A combinatorial library of 60 C- nucleoside analogs was synthesized by sequential coupling of building blocks followed by cyclative cleavage with DBU in an efficient manner. Only DMSO soluble compounds were tested for their modulatory effect against filarial ã-glutamyl cysteine synthetase (g-GCase) and glutathione-S-transeferases (GSTs). Several compounds were found to be weak inhibitors of filarial g-GCase, whereas, most of them stimulated filarial GSTs.
[Back to top] Lead Generation – Enhancing
the Success of Drug Discovery by Investing in the Hit to Lead Process
Alexander Alanin, Matthias Nettekoven, Edward Roberts and Andrew W. Thomas
Improving on the poor success rates in the drug discovery industry requires that knowledge-based decisions are made to advance or stop a lead candidate as early as possible in the discovery process. Failure to make such timely decisions on the rigorous selection of lead candidates has costly time and resource implications in downstream drug development. To meet this challenge dedicated ‘hit to lead’ groups have recently been established in many major pharmaceutical companies, and a key to the success of such groups is establishing a clear consistent process and rigorous metrics for lead quality. The importance of such a “Lead Generation” group within the drug discovery process will be highlighted with the aim of placing a greater level of emphasis in discovering and refining novel lead series with enhanced drug-like properties. This activity is facilitated by the application of productivity enhancing, integrated technologies coupled with the early evaluation of drug-like properties in the lead refinement process to ensure that a balanced activity - properties profile can be attained before committing to a full lead optimisation program. This article will survey the processes and tools employed in the hit to lead process in such a “Lead Generation” group in order to achieve these objectives, emphasising the possible gains in productivity through close, early interactions between chemistry and other expert groups.
[Back to top] Design and Peptide-Based
Validation of Phage Display Antibodies for Proteomic Biochips
N. Stich, G. van Steen and T. Schalkhammer
To validate potential application of phage display-antibody arrays for high-throughput screening on a novel proteomics biochip, we examined the epitopes versus the full protein of glucose-6-phosphatedehydrogenase (G6PD) from yeast. In a predictive approach, we used the Hopp-Woods method and compared the results with antibodies directed against the entire enzyme. In total, 16 peptides of a length of 11 amino acids each fulfilling the desired criteria were identified and synthesized. Subsequently, antibodies against G6PD were raised using a phage display library. Selective interaction of the antibodies with certain peptides facilitated the identification of epitopes predicted by the hydropathic profile. The setup was adapted to a novel biochip system based on surface-enhanced absorption for direct CCD-camera based screening.
[Back to top] Solid-Phase Synthesis of
Heterocyclic Aromates: Applicability towards Combinatorial Chemistry; a Review
E. Gelens, W.J. Koot, W.M.P.B. Menge, H.C.J. Ottenheijm and H. Timmerman
Because of their biological activity,
stability in vivo, the rigid spatial positioning of their substituents, and
their synthetic challenges, heterocyclic aromates continue to be of interest to
both academic and industrial medicinal chemists. Currently, many drug-like
heterocyclic aromates are prepared via solidphase organic chemistry methods.
This review examines the applicability of those methods towards combinatorial
chemistry with respect to the basic demands of such an approach: 1) synthesis,
work-up and subsequent purification should be easily automated enabling the
efficient simultaneous synthesis of large numbers of highly pure compounds in a
minimum amount of time, 2) large diversity among the ligands to be synthesized,
3) high conversion rates of the individual reaction steps, and 4) the use of
commercially available starting materials. Although many methods have been
developed for the synthesis of heterocyclic aromates, very few of the available
methods enable the synthesis of highly diverse heteroaromatic libraries.