Chemical space modulators

D Data Mining module utilizing the novel concept of Chemically Relevant Principal Components to visualize and analyze chemical space of results from ADMET Predictor. 

Since the protein target and the chemical modulator are unknown, for this drug development strategy methodologies are required that lead to structurally complex and diverse small molecules covering a broad region of the so-called chemical space [2, 6]. This is one of the main focuses of diversity-oriented... 

The space dimension can be 2D (shown), ID, 3D, Axial symmetry (ID), or Axial symmetry (2D), Consider first the 2D option. If you double click on the Chemical Engineering Module, the screen changes to Figure D.2. 

As outlined above the chemical structure space accessible to small drug-like molecules is so vast that it cannot be covered by chemical synthesis in a comprehensive and meaningful manner. During evolution nature herself has explored only a tiny fraction of chemical space in the biosynthesis of low molecular weight natural products. The same is true for the evolution of the targets bound and modulated by natural products, for example proteins. It has been estimated that during the evolution of a protein consisting of about 100 amino acids only a tiny fraction of all amino acid combinations could have been biosynthesized. However, in protein evolution, structure is even more conserved than the sequence since similar structures can be formed by very different sequences. Thus the protein structure space explored by nature is limited in size. ... 

In an attempt to improve the inhibition kinetics, a pepticinnamin E library was synthesized to explore the chemical space of the natural product7 Three types of modifications were investigated changes to the N- and C-terminal substituents on the backbone, changes in N-methylation status, and the addition of an N-terminal histidine residue to form an interaction with the active site zinc atom. The inclusion of a histidine residue at the N-terminal peptide position proved favorable and modulation of the N-terminal substituent (i.e., the farnesyl pyrophosphate mimic) proved important for inhibition. Several of the compounds from the library were shown to induce apoptosis in MDCK-f3 tumor cells at concentrations of 100 pmol 1 however, in the case of only one compound could apoptosis be linked to FT inhibition. 

In order to account for the limitations imposed by blood-brain barrier permeability, a further refinement of the concept of drug-likeness is required for compounds intended to modulate central nervous system (CNS) targets. This presentation will center on criteria and processes that can be applied to the de novo design of individual compounds and libraries to increase the odds of structures residing within CNS-accessible chemical space. Application of these principles to the identification and optimization of CNS-targeted leads will be discussed. 

One theoretical issue that has not been fully resolved is that some attractant compounds might also inhibit feeding, especially at higher concentrations, which could also produce dose-response curves similar to those of repellents, and may be responsible for differences seen in olfactometer (where mosquitoes have the space to fly to or to avoid the test chemicals) and module testing (where mosquitoes are in small sealed cells). For example, lemon peel was found to be repellent in module... 

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