Combinatorial Chemists Research Articles

Phyto phamacological importance of Thevetia peruviana: A literature based review

Nature is the best combinatorial chemist and possibly has answers to all diseases of humankind. Till now, natural product compounds discovered from medicinal plants have provided numerous clinically useful drugs. Plant based therapeutics play an important role in the public health care system of any nation. Natural products with medicinal value are gradually gaining importance in clinical research due to their well-known property of no side effects as compared to drugs. In recent years, the growing demand for herbal product has led to a quantum jump in volume of plant metabolite previously with unknown pharmacological activities have been extensively investigated as a source of medicinal agents. Thevetia peruviana Pers. commonly named as “Kaneir or Kaner” is known for its immense application in the treatment of various diseases in the traditional Ayurvedic literature. Plant based therapeutics play an important role in the public health care system of any nation. The plant Thevetia peruviana belongs to the family Apocynaceae. The plants have a significant place in traditional system of medicine of Central and South America and tropical Asia. A number of different classes of secondary metabolites are present in Thevetia peruviana including alkaloids, flavonoids, steroids, cardiac glycosides, terpenoids, tannins, saponins etc. Several researchers had identified various pharmacological activities in different parts of the plant viz. seeds, flowers, bark, fruits, leaves. This review covers detailed ethno pharmacology, toxicology and bioactivities of Thevetia peruvian.

Diversification of Animal Venom Peptides—Were Jellyfish Amongst the First Combinatorial Chemists?

An ocean of data: Huge numbers of protein toxins are found in animal venoms. This diversity is widely believed to have arisen by gene duplication events. However, recent data now challenges this tradition view. Here we highlight how jellyfish could hold the key to unravelling toxin diversification, with a view towards future combinatorial biosynthesis of toxin libraries.

Computational Approaches to Screen Candidate Ligands with Anti- Parkinson’s Activity Using R Programming

It is estimated that by 2050 over 100 million people will be affected by the Parkinson's disease (PD). We propose various computational approaches to screen suitable candidate ligand with anti-Parkinson's activity from phytochemicals. Five different types of dopamine receptors have been identified in the brain, D1-D5. Dopamine receptor D3 was selected as the target receptor. The D3 receptor exists in areas of the brain outside the basal ganglia, such as the limbic system, and thus may play a role in the cognitive and emotional changes noted in Parkinson's disease. A ligand library of 100 molecules with anti-Parkinson's activity was collected from literature survey. Nature is the best combinatorial chemist and possibly has answers to all diseases of mankind. Failure of some synthetic drugs and its side effects have prompted many researches to go back to ancient healing methods which use herbal medicines to give relief. Hence, the candidate ligands with anti-Parkinson's were selected from herbal sources through literature survey. Lipinski rules were applied to screen the suitable molecules for the study, the resulting 88 molecules were energy minimized, and subjected to docking using Autodock Vina. The top eleven molecules were screened according to the docking score generated by Autodock Vina Commercial drug Ropinirole was computed similarly and was compared with the 11 phytochemicals score, the screened molecules were subjected to toxicity analysis and to verify toxic property of phytochemicals. R Programming was applied to remove the bias from the top eleven molecules. Using cluster analysis and Confusion Matrix two phytochemicals were computationally selected namely Rosmarinic acid and Gingkolide A for further studies on the disease Parkinson's.

ChemInform Abstract: Lipophilic Propanediamines: New Building Blocks for Combinatorial Chemistry

Abstract Combinatorial chemists need building block libraries where molecular diversity is taken into account. For this purpose, we describe the synthesis of a library of 2-alkyl and 2-alkoxypropanediamines for which a large scale of lipophilicity is investigated.

Diversity-oriented fluorescence library approaches for probe discovery and development

Diversity-oriented fluorescence library approaches have significantly accelerated the development of new sensors. By making use of combinatorial chemistry and high-throughput screening, they can circumvent our limitations in designing probes for particular recognition processes. Combinatorial chemists have proved how to derivatize fluorogenic scaffolds, tune their photophysical spectra and adjust their properties (from cell permeability to quantum yields) to generate libraries of potential sensors. Several platforms (in vitro assays, cell-based imaging) have also been optimized to screen these libraries in a high-throughput manner, and with the recent progress in image acquisition and analysis, their scope has been expanded toward more diverse and demanding biological systems. Supported by successful examples of fluorescent sensors for biomolecules, proteins, or even phenotypes, this review (together with a video abstract) stresses the important role that diversity-oriented approaches will continue to play in probe development in the near future.

New molecular scaffolds for the design of Mycobacterium tuberculosis type II dehydroquinase inhibitors identified using ligand and receptor based virtual screening

Using ligand and receptor based virtual screening approaches we have identified potential virtual screening hits targeting type II dehydroquinase from Mycobacterium tuberculosis, an effective and validated anti-mycobacterial target. Initially, we applied a virtual screening workflow based on a combination of 2D structural fingerprints, 3D pharmacophore and molecular docking to identify compounds that rigidly match specific aspects of ligand bioactive conformation. Subsequently, the resulting compounds were ranked and prioritized using receptor interaction fingerprint based scoring and quantitative structure activity relationship model developed using already known actives. The virtual screening hits prioritized belong to several classes of molecular scaffolds with several available substitution positions that could allow chemical modification to enhance binding affinity. Finally, identified hits may be useful to a medicinal chemist or combinatorial chemist to pick up the new molecular starting points for medicinal chemistry optimization for the design of novel type II dehydroquinase inhibitors.

Design of Multi‐Component Reactions: From Libraries of Compounds to Libraries of Reactions

AbstractMulti‐Component Reactions (MCRs) constitute a methodology to shorter syntheses of natural products or complex molecules similar to natural. Due to the large number of accessible compounds and other advantages, this type of chemistry has become very popular in the community of combinatorial chemists. In the last 5 years combinatorial chemistry is has evolved from the synthesis of libraries based on one scaffold to the synthesis of structurally diverse compounds, better known as diversity‐oriented synthesis. Following this trend, the design of MCRs is becoming a tool kit for chemists to explore chemistry space broadly with complex and diverse structures. Various approaches to the creation of novel MCRs including “union of MCRs”, “substrate design”, and “reaction operator” are discussed here.

Molecular Recognition of Cyclic-Nucleotides and Current Sensors for Their Detection

This work briefly describes available sensors for cAMP and cGMP. Many sensors are based on derivatization of naturally occurring products such as immunoglobulins, protein kinases, etc. Only a few published works deal with chemosensors, which are built up by "total" chemical synthesis. This field stays opened for combinatorial chemist. The best sensors are protein kinases genetically modified with mutants of green fluorescent protein, which allow screening of entire cell cultures.

Tarantulas: eight-legged pharmacists and combinatorial chemists

Tarantula venoms represent a cornucopia of novel ligands for a variety of cell receptors and ion channels. The diversity of peptide toxin pharmacology has been barely explored as indicated by pharmacological, toxicological and mass spectrometry investigations on more than 55 tarantula venoms. MALDI-TOF MS analysis reveals that the pharmacological diversity is based on relatively small size peptides, which seem to fall into a limited number of structural patterns. Properties and biological activities of the 33 known peptide toxins from tarantula venoms are described. Most known toxins conform to the Inhibitory Cystine Knot (ICK) motif, with differences in the length of intercysteine loops. Recently described peptides show that tarantula toxins can fold according to an elaboration of the Disulfide-Directed β-Hairpin (DDH) motif which is also the canonical motif for the ICK fold. The ICK fold itself offers many variations leading to differing toxin properties. Examination of pharmacological data gives insights on the possible conserved site of action of toxins acting on voltage-gated ion channels and other toxins acting by a pore-blocking mechanism. Structure-activity data shows the versatility of the toxin scaffolds and the importance of surface features in the selectivity and specificity of these toxins. Tarantulas appear to be a good model for the discovery of novel compounds with important therapeutic potential, and for the study of the molecular evolution of peptide toxins.

Ketenes in Polymer-Assisted Synthesis

For Abstract see ChemInform Abstract in Full Text.

Design of focused and restrained subsets from extremely large virtual libraries

With the current and ever-growing offering of reagents along with the vast palette of organic reactions, virtual libraries accessible to combinatorial chemists can reach sizes of billions of compounds or more. Extracting practical size subsets for experimentation has remained an essential step in the design of combinatorial libraries. A typical approach to computational library design involves enumeration of structures and properties for the entire virtual library, which may be unpractical for such large libraries. This study describes a new approach termed as on the fly optimization (OTFO) where descriptors are computed as needed within the subset optimization cycle and without intermediate enumeration of structures. Results reported herein highlight the advantages of coupling an ultra-fast descriptor calculation engine to subset optimization capabilities. We also show that enumeration of properties for the entire virtual library may not only be unpractical but also wasteful. Successful design of focused and restrained subsets can be achieved while sampling only a small fraction of the virtual library. We also investigate the stability of the method and compare results obtained from simulated annealing (SA) and genetic algorithms (GA).

Ketenes in polymer-assisted synthesis.

Since its inception, ketene chemistry has developed into a unique and well-established source of useful transformations for conventional synthetic organic chemistry. It is, therefore, not surprising that soon after their movement from the realm of peptide and peptoid libraries to that of small molecules, combinatorial chemists have sought the benefits of ketene chemistry to satisfy their own synthetic needs. The ability of these versatile molecules to undergo reactions with nucleophiles, and to participate in cycloadditions and cyclocondensations, has been utilized for the preparation of diverse heterocyclic compounds, and has added to the advantages of polymer-assisted synthesis for rapid purification. Different types of ketenes and different methods for their generation have been involved, which illustrates the potential diversity of the chemistry. There is now a better grasp of the effect of the fragility of these sometimes transient molecules on the reactions involving solid supports, and this augurs well for the application of some of the more recent developments in ketene chemistry to the generation of small-molecule libraries.

Size Doesn't Matter: Scaffold Diversity, Shape Diversity and Biological Activity of Combinatorial Libraries

Among questions of significant interest to the pharmaceutical industry are the relative merits of screening numerous libraries of moderate size (100,000 members) of a limited selection of chemotypes. Using a newly developed computational method to assess the diversity in molecular shape associated with different compound sets, we have shown that single-scaffold libraries, irrespective of their size, are restricted to a limited range of molecular shapes, whereas collections of several small libraries around distinct chemical scaffolds can produce a higher degree of shape diversity. A comparison of the molecular shape distribution patterns associated with different MDDR (MDL® Drug Data Report) subsets of known biological activities corroborates the intuitive notion that molecular shape is intimately linked to biological activity, and that a high degree of shape (hence scaffold) diversity in screening collections will increase the odds of addressing a broad range of biological targets. In order to cope with the challenge of assembling a portfolio of small libraries around various central scaffolds in a reasonable amount of time, the combinatorial chemist must now, more than ever, seek to optimize the synthetic outcome with respect to the efforts in terms of chemistry set-up and validation.

Microwave-Assisted Solid-Phase Organic Synthesis (MA-SPOS) of Oxazolidinone Antimicrobials

Publisher Summary Microwave-assisted solid-phase organic synthesis (MA-SPOS) is a valuable methodology for the rapid synthesis of novel and diverse chemical entities. The recent advances in microwave equipment have provided homogeneous microwave heating in safe and reliable instruments for use in the chemistry laboratory. A MA-SPOS of the antimicrobial oxazolidinone pharmacophore is described in this chapter as a demonstration of the utility of this emerging technology towards drug discovery. The optimization process and full experimental details for the synthesis of a small library of oxazolidinones are exemplified. The oxazolidinones comprise a unique class of potent antibacterial agents. MA-SPOS enables the combinatorial chemist to break through the solid-phase synthetic chemistry optimization bottleneck and develop new reaction conditions in hours or days rather than weeks or months. The rapid production of the libraries of novel compounds has thus, been enabled by synergizing the best aspects of MA chemistry and SPOS.

Combinatorial Chemistry: A Guide for Librarians.

In the 1980s a need to synthesize many chemical compounds rapidly and inexpensively spawned a new branch of chemistry known as combinatorial chemistry. While the techniques of this rapidly growing field are used primarily to find new candidate drugs, combinatorial chemistry is also finding other applications in various fields such as semiconductors, catalysts, and polymers. This guide for librarians explains the basics of combinatorial chemistry and elucidates the key information sources needed by combinatorial chemists.

Design of virtual combinatorial libraries.

AbstractLast year marked the completion of the sequencing effort on the human genome. Advances in the fields of genomics and bioinformatics are widely expected to bring forth a large number of new biochemical targets for drug design by linking specific diseases to single genes or collections thereof. The pharmaceutical and biotechnology sector is now likely to become one of the most active industrial fields in the new century. A dramatic increase in the number of pharmaceutical targets in the near future would create a bottleneck of sorts at the stage of pharmaceutical drug discovery. Historically, this field has used a serial process, screening and optimizing compounds one at a time. However, the advent of combinatorial chemistry and high-throughput screening has significantly altered the face of drug discovery. Rapid generation and screening of combinatorial libraries has become commonplace in both industry and academia; with the ever-growing offering of organic reagents along with the vast palette of organic reactions, the chemical space accessible to combinatorial chemists has dramatically expanded. The application of combinatorial technology, however, is not without a potential caveat—even as the cost of synthesis and testing of a single chemical entity has fallen, it skyrockets when multiplied by the thousands or millions of combinatorial library members. Some of the potential solutions include (i) use of the three-dimensional target structure information in the design process; (ii) application of pharmacophore and quantitative structure-activity relationship (QSAR) methods to focus on libraries that most closely resemble screening hits; and (iii) reduction in the scale on which both medicinal chemistry and screening are currently performed. These solutions imply a need for a rational approach to reducing library size, custom izing the library for a given target, and more efficient in silico screening of a library (or, potentially, multiple libraries) of compounds against a large number of targets of interest. The challenge in accomplishing these goals is in being able to reduce the library while increasing the potential hit rate of individual library members.KeywordsLibrary DesignVirtual LibraryMolar RefractivityLibrary MemberAvailable Chemical DirectoryThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Process Development Automation: An Evolutionary Approach

As it matures in the research laboratory as a tool for the combinatorial chemist, automation is now moving into the development area. However, the classical combinatorial robot is not appropriate for all development activities, as it is primarily a serial device and lacks on-line analysisoften a key requirement for high-speed development. Automation equipment is becoming commercially available to cover all three development stagesroute scouting, process optimisation, and final process definitionbut it is often highly specific, expensive, complex and may not offer a complete solution. In contrast, standard laboratory equipment already contains some automated capabilities but is normally unused in our automation strategies. This presentation will discuss issues related to a stepwise and unified approach to automation across all three stages, using existing standard laboratory equipment. Examples from diverse areas including calorimetry, DoE, crystallisation studies, and plant simulation will be discussed along with equipment and computer issues. Inexpensive commercial software is now available to control these systems, or software can be developed using modern visual development environments. This is not rocket scienceyou have the technology!

Papers presented at the 24th annual meeting of the British Mass Spectrometry Society. 12-15 September 1999.

The 24th Annual Meeting of the British Mass Spectrometry Society was held at the University of Reading and attracted over three hundred delegates from all fields of mass spectrometry and related disciplines. The vibrant programme consisted of eight oral sessions, wide- ranging poster sessions and workshops; the final day of the meeting focused on Biomacromolecules, encompassing non-covalent interactions, oligosaccharides, oligonucleotides and proteomics. The previous days' topics covered Instrumental Developments, Separations, Fundamentals, Combinatorial Chemistry, Synthetic Polymers, Environmental and Inorganic mass spectrometry. The meeting was opened by Professor John Monaghan (Chair) and followed by an address from Professor Keith Jennings who gave a brief eulogy for the late Professor Allan Maccoll. Keith gave an overview of the contributions Allan made to mass spectrometry, in particular noting that he was one of the Founders of our Society. Professor Nico Nibbering then delivered the Maccoll Lecture entitled “Recent Chemical Research with the Use of Mass Spectrometry” in which he stressed the importance, to those of the community involved in the study of large biomolecules, of having a good understanding of the fundamentals of the subject. Professor Graham Cooks had the unenviable task of following this splendid lecture but in his usual enthusiastic style delivered a far reaching talk illustrating the potential of ion trap technology. Opening the Environmental session Dr Susan Richardson (U.S. EPA) showed how mass spectrometry played a key role in maintaining the quality of drinking water when so many alternative water disinfectant systems are being introduced that can give rise to Disinfection By-Products. The longest question and answer session of the meeting followed and the delegates were left with no illusions about the need for monitoring and treatment of their water supplies. Two of the keynote/plenary presentations were given by non-mass spectrometrists, Professor Peter Myers and Dr John Reader. Peter opened the Separations session with an in depth and revealing talk on different packing materials and HPLC columns while John covered the need for mass spectrometry from the viewpoint of the combinatorial chemist. The Michael Barber Award for best presentation by young scientists (under 27 years) went to Jennie Lill of Nottingham Trent University for her poster entitled “Metal complexation studies of MHC associated peptides by electrospray mass spectrometry”. From a personal viewpoint one of the most informative and useful presentations was given by Professor Jim Scrivens where he presented a detailed description of synthetic polymer analysis. The workshop sessions were also well attended, covering MS–MS, MALDI and in the New Users workshop Dr Bob Boyd discussed the art of paper writing. The social programme was well attended and included a Firework display to mark our final meeting of the Millennium. Most delegates gave favourable feedback on the content of the meeting and especially liked the expanded and dedicated Manufacturers' Exhibition. We look forward to out 25th Annual Three Day Meeting on 8–12 September 2001 at the University of Southampton with renewed vigour for the future of our Society and its members. The delegates were invited to submit full papers of their presentations and the following are representative of the work presented at the Reading Meeting G. J. Langley University of Southampton, UK January 2000

Evaluation of reagent-based and product-based strategies in the design of combinatorial library subsets.

With the current and ever-growing offering of reagents along with the vast palette of organic reactions, virtual libraries accessible to combinatorial chemists have dramatically increased in size. Yet, extracting representative subsets for experimentation is an essential step in the design of combinatorial libraries. There has been some controversy whether it is necessary to consider product properties, at some computational expense, or whether sufficiently representative sets can be identified from considerations of the reagent space alone. This study compares the efficiency of reagent-based selections and that of product-based combinatorial subsetting in the identification of representative library subsets. Quantitative estimates reported herein show that the advantage of working in product space is descriptor dependent. For some descriptors, product-based approaches provide a distinct advantage, whereas for others results from reactant pools offer comparable results. Hence the behavior of descriptors, in mapping diversity from reagent space to product space, should be investigated prior to embarking into lengthy product-based considerations. Several classes of descriptors are studied including two-dimensional fingerprints (ISIS and Daylight) and physicochemical descriptors.

A New Automation Tool for Medicinal and Combinatorial Chemists

A New Automation Tool for Medicinal and Combinatorial Chemists