Molecular design metabolism

Melendes-Hevia E, Waddell TG, Shelton ED Optimization of molecular design in the evolution of metabolism the glycogen molecule. BiochemJ 1993 295 477. 

Bioavailability is defined as the portion or fraction of a chemical that is available for biological action and is influenced by several factors including the molecular size and charge of a molecule, structural features of membranes, first pass metabolism, and therefore, bio availability can be influenced by the molecular structure of a chemical. This situation presents an opportunity for molecular designers to manipulate a chemical s structure to decrease bioavailability and consequently hazard. If the availability of a molecule can be decreased, the amount of chemical at the site of action is decreased which leads to decreased toxicity. 

Boyer, S. and Zamora, I. (2002) New methods in predictive metabolism. Journal of Computer-Aided Molecular Design, 16 (5/6), 403 113. 

The number of possible mechanisms by which a chemical can exert a toxic effect on humans and other species is staggering. As shown here, some are well understood, but further elucidation of mechanisms of toxic action is direly needed to propagate the field of safe chemical design. However, this cannot be a reason for molecular designers not to attempt to consider the most likely reactivity of a chemical inside an organism, and to make an effort to minimize rationally either its bioavailability, metabolic activation, or ligand binding interactions with biomolecules. 

Several databases of published biotransformations are commercially available, such as Molecular Design Ltd s Metabolite and the Accelerys Metabolism Database (formerly produced by Synopsis). The former is quite extensive, and contains in vivo and in vitro biotransformation summaries from the literature, while the latter has as its core information based on the U.K. Royal Society of Chemistry s Biotransformations series (Hawkins, 1988-1996) supplemented by additional data from the literature. Both systems are searchable by reaction type. The intelligent use of such databases provides much valuable information on likely metabolic profile. 

Metabolites of pesticidal products in the environment often give useful hints for molecular designs. Studying the metabolic pathway in plants we saw that imidacloprid (9) decomposed to the olefinic metabolite (29) through the hydroxylated intermediate... 

In this chapter, molecular factors affecting structural behavior of fat polymorphism are discussed in terms of internal influences of the TAG molecules. In particular, the influences of fatty acid compositions and their positions connected to glycerol carbons on the polymorphism of fat crystals are of primary concern. It has been known that the fats with simple and symmetric fatty acid compositions tend to exhibit typical oc, P, and P forms, whereas those with asymmetric mixed-acid moieties often make the P form more stable (1,9). In the mixed-acid TAG containing unsaturated fatty acid moieties, the number and conformation of the double bond, cis or trans, give rise to remarkable influences on the polymorphic structures (10-12). The TAG containing different saturated fatty acids with different chain-lengths also revealed quite diversified polymorphism (13-15). Therefore, it may be worthwhile now to discuss the molecular aspects of the polymorphism of fats. This consideration may also be a prerequisite for molecular design of structured fats, in combination with nutritional and metabolic properties. 

Molecular designs that would lead to efficient metabolic degradation and/or excretion patterns totally nondependent on enzyme catalysis.21 Such a drug would always exhibit... 

Lewis, M.L. and Cucurull-Sanchez, L. (2009) Structural pairwise comparisons of HLM stability of phenyl derivatives introduction of the Pfizer metabolism index (PMI) and metabolism-lipophilicity efficiency (MLE). Journal of Computer-Aided Molecular Design, 23 (2), 97-103. 

The prevalence of the heme in O2 metabolism and the discovery in the 1960s that metallophthalocyanines adsorbed on graphite catalyze four-electron reduction of O2 have prompted intense interest in metaUoporphyrins as molecular electrocatalysts for the ORR. The technological motivation behind this work is the desire for a Pt-ffee cathodic catalyst for low temperature fuel cells. To date, three types of metaUoporphyrins have attracted most attention (i) simple porphyrins that are accessible within one or two steps and are typically available commercially (ii) cofacial porphyrins in which two porphyrin macrocycles are confined in an approximately stacked (face-to-face) geometry and (iii) biomimetic catalysts, which are highly elaborate porphyrins designed to reproduce the stereoelectronic properties of the 02-reducing site of cytochrome oxidase. 

In the following section, the calculation of the VolSurf parameters from GRID interaction energies will be explained and the physico-chemical relevance of these novel descriptors demonstrated by correlation with measured absorption/ distribution/metabolism/elimination (ADME) properties. The applications will be shown by correlating 3D molecular structures with Caco-2 cell permeabilities, thermodynamic solubilities and metabolic stabilities. Special emphasis will be placed on interpretation of the models by multivariate statistics, because a rational design to improve molecular properties is critically dependent on an understanding of how molecular features influence physico-chemical and ADME properties. 

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