Lead compounds, conformational analysis

This approach of combining shape-matching and conformahonal analysis proved a useful complement to HTS. Some of the compounds identified by the computational screen were not detected in the original experimental screen. This was because their relative weak activity was difficult to separate from the noise of the assay. Nonetheless, these compounds had different scaffolds (i.e. were lead-hops ) compared to the previously known inhibitor. The key contribution from conformational analysis was that the newly discovered inhibitors were not found by the corresponding searches based on 2D methods. 

We also performed a single-crystal X-ray structure analysis of this lead compound. The solid state structure of this compound depicted in Fig. 3-15 shows a half-boat-like ( sofa ) conformation with the 9-phenanthryl group in a quasi-axial or r/Mf/.v/-flagpole position, and the a, 3-unsaturated exocyclic ester in a s-cis conformation. This cleft-like conformation is advantageous for the creation of centers with a high recognition ability, since one enantiomer fits in better than the other thus leading to selectivity. 

When a validated hit is selected as a promising lead compound, its physicochemical profile must be studied in detail. Sophisticated in silica approaches such as 3D lipophilicity predictions coupled with extensive conformational analysis [49, 50,135,146] and molecular field interactions (MIFs) [147-150] could be helpful to better interpret the detailed experimental investigations of their ionization constants by capillary electrophoresis or potentiometric titrations [151, 152] and their lipophilicity profiles by potentiometry [153]. However, these complex approaches cannot be performed easily on large number of compounds and are generally applied only on the most promising compounds. 

Fourier-Transform Infrared (FTIR) spectroscopy as well as Raman spectroscopy are well established as methods for structural analysis of compounds in solution or when adsorbed to surfaces or in any other state. Analysis of the spectra provides information of qualitative as well as of quantitative nature. Very recent developments, FTIR imaging spectroscopy as well as Raman mapping spectroscopy, provide important information leading to the development of novel materials. If applied under optical near-field conditions, these new technologies combine lateral resolution down to the size of nanoparticles with the high chemical selectivity of a FTIR or Raman spectrum. These techniques now help us obtain information on molecular order and molecular orientation and conformation [1],... 

On the other hand, we may desire a compound which has the activity of a particular lead, but is of apparently different structure. That is a new lead. In this case we would try to design compounds which possess different chemical structures but maintain identical steric, transport, and reactivity properties. It was for this purpose that we have developed a computerized tool, called MOLY, which can assist in the molecular design problem. In this paper we will briefly review what this system is and detail our efforts to parameterize the conformational analysis section of MOLY. 

The preferred conformations of carbonyl compounds, like 1-alkenes, are eclipsed rather than bisected, as shown below for ethanal and propanal. The barrier for methyl group rotation in ethanal is 1.17kcal/mol. Detailed analysis has indicated that small adjustments in molecular geometry, including a-bond lengthening, must be taken into account to quantitatively analyze the barrier. The total barrier can be dissected into nuclear-nuclear, electron-electron, nuclear-electron, and kinetic energy (At), as described in Topic 1.3 for ethane. MP2/6-311+G (Mf,2p) calculations lead to the contributions tabulated below. The total barrier found by this computational approach is very close to the experimental value. Contributions to the ethanal energy barrier in kcal/mol are shown below. 

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