Hartmuth C. Kolb

Bio: Hartmuth C. Kolb is an academic researcher from Novartis. The author has contributed to research in topics: Drug discovery & Sialyl-Lewis X. The author has an hindex of 10, co-authored 13 publications receiving 1060 citations.

Drug Discovery Today

Abstract: In recent years, tools for the development of new drugs have been dramatically improved. These include genomic and proteomic research, numerous biophysical methods, combinatorial chemistry and screening technologies. In addition, early ADMET studies are employed in order to significantly reduce the failure rate in the development of drug candidates. As a consequence, the lead finding, lead optimization and development process has gained marked enhancement in speed and efficiency. In parallel to this development, major pharma companies are increasingly outsourcing many components of drug discovery research to biotech companies. All these measures are designed to address the need for a faster time to market. New screening methodologies have contributed significantly to the efficiency of the drug discovery process. The conventional screening of single compounds or compound libraries has been dramatically accelerated by high throughput screening methods. In addition, in silico screening methods allow the evaluation of virtual compounds. A wide range of new lead finding and lead optimization opportunities result from novel screening methods by NMR, which are the topic of this review article.

Development of tools for the design of selectin antagonists

Abstract: A molecular modeling tool for the rational design of E-selectin antagonists based on the lead structure sialyl Lewisx has been developed. The binding affinity to the receptor is considerably influenced by the entropy and consequently by the antagonist's ability to place its pharmacophores in an optimal spatial arrangement, i.e., by its preorganization for binding. The computational model assesses the preorganization of a potential selectin antagonist with the aid of Monte Carlo (jumping between wells)/stochastic dynamics [MC(JBW)/SD] simulations. The model has been validated by correlating preorganization and bioactivity of several selectin antagonists. The results suggest that only preorganized compounds are likely to bind to E-selectin.

Drug discovery today.

Abstract: In recent years, tools for the development of new drugs have been dramatically improved. These include genomic and proteomic research, numerous biophysical methods, combinatorial chemistry and screening technologies. In addition, early ADMET studies are employed in order to significantly reduce the failure rate in the development of drug candidates. As a consequence, the lead finding, lead optimization and development process has gained marked enhancement in speed and efficiency. In parallel to this development, major pharma companies are increasingly outsourcing many components of drug discovery research to biotech companies. All these measures are designed to address the need for a faster time to market. New screening methodologies have contributed significantly to the efficiency of the drug discovery process. The conventional screening of single compounds or compound libraries has been dramatically accelerated by high throughput screening methods. In addition, in silico screening methods allow the evaluation of virtual compounds. A wide range of new lead finding and lead optimization opportunities result from novel screening methods by NMR, which are the topic of this review article.

Recent progresses in the glycodrug area

Abstract: A new molecular modelling tool for analysing the pre-organization of sialyl Lewis' mimics for binding to E-selectin has been developed. The pre-organization is quantified as the probability for being in the bioactive window of torsional space. The probability data can be correlated with bioactivity, since carbohydrate mimics which populate the bioactive window are likely to be active towards E-selectin, whereas compounds which do not populate the bioactive window are generally inactive. Work is in progress with the aim to further refine this model and to develop quantitative structure activity relationships using the probability data as descriptors. The computational tool has guided our search for new and more active E-selectin antagonists. One of our most active carbohydrate mimics, the cyclohexyl derivative 95, combines an over ten-fold higher affinity towards E-selectin with a considerably lower molecular weight and a lower hydrophilicity compared to sialyl Lewis'. Numerous diseases and pathological situations are related to excessive influx of leukocytes into the tissue.' The complex process which leads to the recruitment of leukocytes from the blood stream is initiated by the interaction of carbohydrates on the leukocyte's cell surface and the selectins. The latter are a family of C- type lectins, of which P- and E-selectin are expressed on endothelial cells after stimulation while L-selectin is present on leukocyte cell surfaces. The carbohydrate epitope recognized by all selectins, albeit with different affinities, is the tetrasaccharide sialyl Lewis'. A new strategy for the treatment of inflammatory and respiratory diseases is based on the inhibition of the carbohydratelselectin interactions.' Currently, we are searching for low molecular weight carbohydrate mimics which are designed to block the selectin binding site in order to inhibit the process of leukocyte recruitment. A prerequisite for the rational design of high affinity selectin antagonists is a thorough understanding of the role of all the functional groups' and their spatial orientation in the lead structure, sialyl Lewis'. Figure 1 summarizes the functional groups involved in binding yigure la) and their orientation yigure lb) in the 'bioactive conformation', as established by transfer-NOE NMR experiment^.^

Natural Products as Sources of New Drugs over the Last 25 Years

Abstract: This review is an updated and expanded version of two prior reviews that were published in this journal in 1997 and 2003. In the case of all approved agents the time frame has been extended to include the 251/2 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 155 small molecules, 73% are other than “S” (synthetic), with 47% actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the antiinfective area ...

Chaotic Mixer for Microchannels

Abstract: It is difficult to mix solutions in microchannels. Under typical operating conditions, flows in these channels are laminar—the spontaneous fluctuations of velocity that tend to homogenize fluids in turbulent flows are absent, and molecular diffusion across the channels is slow. We present a passive method for mixing streams of steady pressure-driven flows in microchannels at low Reynolds number. Using this method, the length of the channel required for mixing grows only logarithmically with the Pe «clet number, and hydrodynamic dispersion along the channel is reduced relative to that in a simple, smooth channel. This method uses bas-relief structures on the floor of the channel that are easily fabricated with commonly used methods of planar lithography.

Nanoparticles in photodynamic therapy.

Abstract: Sasidharan Swarnalatha Lucky,†,§ Khee Chee Soo,‡ and Yong Zhang*,†,§,∥ †NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore, Singapore 117456 ‡Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore 169610 Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore 117576 College of Chemistry and Life Sciences, Zhejiang Normal University, Zhejiang, P. R. China 321004

Chemistry and Biology Of Multicomponent Reactions

Abstract: Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, … 7, where most of the atoms of the starting materials are incorporated in the final product.1 Several descriptive tags are regularly attached to MCRs (Fig. 1): they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in one-step instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2 Therefore MCRs are often a useful alternative to sequential multistep synthesis. Open in a separate window Figure 1 Above: multistep syntheses can be divergent (sequential) or convergent; below: in analogy MCR reactions are convergent and one or two component reactions are divergent or less convergent.