Searching Small Molecules

A molecular dynamics simulation samples the phase space of a molecule (defined by the position of the atoms and their velocities) by integrating Newton s equations of motion. Because MD accounts for thermal motion, the molecules simulated may possess enough thermal energy to overcome potential barriers, which makes the technique suitable in principle for conformational analysis of especially large molecules. In the case of small molecules, other techniques such as systematic, random. Genetic Algorithm-based, or Monte Carlo searches may be better suited for effectively sampling conformational space. 

Judson R S, W P Jaeger, A M Treasurywala and M L Peterson 1993. Conformational Searching Methods for Small Molecules. 2. Genetic Algorithm Approach. Journal of Computational Chemistry 14 1407-1414. 

Once the least-squares fits to Slater functions with orbital exponents 1.0 are available, fits to Slater functions with other orbital exponents can be obtained by simply multiplying the a s in the above three equations by It remains to be determined what Slater orbital exponents to use in electronic structure calculations. The two possibilities may be to use the best atom expo-nents( = 1.0 for H, for example) or to optimize exponents in each calculation. The best atom exponents might be a rather poor choice for molecular environments, and optimization of nonlinear exponents is not practical for large molecules, where the dimension of the space to be searched is very large. Acompromise is to use a set of standard exponents where the average values of exponents are optimized for a set of small molecules. The recommended STO-3G exponents are... 

The systematic, or grid, search is only possible for small molecules. For larger systems tlrere are methods which can be used for perturbing a geometry from a local minimum to another minimum. Some commonly used methods for conformational sampling are ... 

There were essentially three reasons for this opposition. Firstly, many macromolecular compounds in solution behave as colloids. Hence they were assumed to be identical with the then known inorganic colloids. This in turn implied that they were not macromolecular at all, but were actually composed of small molecules bound together by ill-defined secondary forces. Such thinking led the German chemist C. D. Harries to pursue the search for the rubber molecule in the early years of the twentieth century. He used various mild degradations of natural rubber, which he believed would destroy the colloidal character of the material and yield its constituent molecules, which were assumed to be fairly small. He was, of course, unsuccessful. 

The search for adsorptive applications of MOFs has up to now mainly focused on the storage of small molecules in gas phase, for instance, H2, CO2, CH4, or NO [46, 92, 93]. This section focuses on the application of MOFs for adsorptive separation of larger molecules and in the hquid phase, a domain in which their potential only recently has been recognized (Figure 4.3). 

Fragment screening by NMR was applied recently in the search of non-peptidic small molecule inhibitors. Two scaffolds (13) and (14), which bind the enzyme at the S1-S3 and the S2 binding site respectively, as shown by chemical shift perturbation, were linked together to yield competitive inhibitors such as (15) with micromolar IC50 values [158]. There have been no reports of non-peptidic inhibitors with potency and pharmacokinetics similar to the peptidic or peptidomimetic inhibitors described above. 

Although most work to date has focused on the enzyme inhibition aspect, it is possible that the monoclonal VAP-1 antibody discussed above may well be closer to the clinic. The task of designing small molecules to interfere with cell-cell recognition is certainly feasible, but this will not be a trivial effort, more akin to the search for selective selectin antagonists which has proven to be very challenging. As confidence grows in the pharmaceutical industry that SSAO/VAP-1 is a validated target, it is inevitable that considerable resources will be directed to all avenues to block the functional action of this protein. 

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