Drug design - Wikipedia
Design, Synthesis, and Structure-Activity Relationship Study of (2)Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of. Drug design, often referred to as rational drug design or simply rational design, is the inventive . In practice it still takes several iterations of design, synthesis, and testing before an optimal drug is discovered. Alternatively, a quantitative structure-activity relationship (QSAR), in which a correlation between calculated. Study on the design, synthesis and structure-activity relationships of new Drug; Drug Design*; Enzyme Inhibitors/chemical synthesis; Enzyme.
These methods use linear regressionmachine learningneural nets   or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target. The reality is that present computational methods are imperfect and provide, at best, only qualitatively accurate estimates of affinity. In practice it still takes several iterations of design, synthesis, and testing before an optimal drug is discovered.What is STRUCTURE-ACTIVITY RELATIONSHIP? What does STRUCTURE-ACTIVITY RELATIONSHIP mean?
Computational methods have accelerated discovery by reducing the number of iterations required and have often provided novel structures. For structure-based drug design, several post-screening analyses focusing on protein-ligand interaction have been developed for improving enrichment and effectively mining potential candidates: Selecting candidates by voting of multiple scoring functions May lose the relationship between protein-ligand structural information and scoring criterion Represent and cluster candidates according to protein-ligand 3D information Needs meaningful representation of protein-ligand interactions.
Types[ edit ] Drug discovery cycle highlighting both ligand-based indirect and structure-based direct drug design strategies.
There are two major types of drug design. The first is referred to as ligand-based drug design and the second, structure-based drug design. These other molecules may be used to derive a pharmacophore model that defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target. Alternatively, a quantitative structure-activity relationship QSARin which a correlation between calculated properties of molecules and their experimentally determined biological activity, may be derived.
These QSAR relationships in turn may be used to predict the activity of new analogs. Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist.
Alternatively various automated computational procedures may be used to suggest new drug candidates. This method is known as virtual screening.
A second category is de novo design of new ligands.
Design, synthesis, and structure-activity-relationship of a novel series of CXCR4 antagonists.
In this method, ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner.
These pieces can be either individual atoms or molecular fragments. The key advantage of such a method is that novel structures, not contained in any database, can be suggested. However, there may be unoccupied allosteric binding sites that may be of interest. Furthermore, it may be that only apoprotein protein without ligand structures are available and the reliable identification of unoccupied sites that have the potential to bind ligands with high affinity is non-trivial.
Subsequently, the cells were incubated with LPS 0. Macrophages were plated at a density of 5. SAR of benzene ring B: This indicates that a methoxy group at this position is preferred for the activity. Comparatively, electron-withdrawing substituted compounds exhibited very weak or no activity.
This suggests that mono- or di-substitution of electron-withdrawing functional groups on benzene ring B is not tolerated. Optimization at the benzene ring A of 1-indanone to obtain 8f To further improve the anti-inflammatory activity and, in particular, inhibition on IL-6, we next directed our optimization effort to modify the benzene ring A of 4d by introducing different types of groups. These results are shown in Table 2. Incorporation of hydroxyl group at the 7- and 5-position of benzene ring A led to compounds 8a and 8b, which, respectively, showed either markedly reduced or no activity.
Meanwhile, etherification at the 4- 5- 6- or 7-hydroxyl group with O-propyl or O-isopropyl moieties produced compounds 8g-8n. This result indicates that the three-carbon chain alkoxy groups at the C-7 position for 8g and 8k were beneficial to the activity. Further screening of substituents around 4d revealed that incorporation of various substituted amino groups at the o-position on the phenyl ring provided compounds 8o-8s. Except for 8s, which has an acetylamino group on the benzene ring, these compounds exhibited a significantly decreased anti-inflammatory ability Illustration of the structure—activity relationship of these 2-benzylideneindanone derivatives is presented in Figure 2.
Figure 2 Structure—activity relationships of 2-benzylideneindanone derivatives. As shown in Table 2all of these compounds showed no significant toxicity in hepatic cells, indicating that they are relatively safe.
MPMs were pretreated with compounds in a series of concentrations 1. These results further support the potential of these compounds as anti-inflammatory agents.
MPMs were plated at a density of 5. Cells were pretreated with compounds in a series concentration of 1. The results were presented as the percentage of LPS control. Macrophages were treated with LPS 0. In particular, compound 8f was the most active compound in inhibiting mRNA expressions of those inflammatory mediators. These data provide evidence for the anti-inflammatory effect of 2-benzylideneindanones 4d, 8f, and 8g, which partly affect the cytokine profile at the mRNA level. Figure 4 Active compounds inhibited the inflammatory genes expression and intracellular inflammatory factor by LPS.
F The cell lysate level of the cytokine IL LPS-induced ALI is characterized by rapid alveolar injury, vascular leakage, lung inflammation, neutrophil accumulation, and induced cytokines production, leading to lung edema.
Compound 8f, which demonstrated the highest activities and low cytotoxicity, was selected for this study. The details of animal experiments were described in the experimental section.