Abstract
Complement anaphylatoxin 5a (C5a) has been recognized as a potent therapeutic target for anti-inflammatory therapy, thus, blocking the action of C5a on its binding receptors may provide an effective treatment of a variety of inflammatory diseases. However, there have been few clinically available non-peptide C5a receptor antagonists disclosed at present. In pursuit of better anti-inflammatory drugs, quantitative structure–activity relationship studies were carried out in a series of non-peptide C5a receptor antagonists with binding activity using different physicochemical descriptors. The conventional best 2D-QSAR models were developed using a training set of 35 molecules and an external test set of 8 molecules by genetic function approximation (GFA) and stepwise multiple linear regression (Stepwise-MLR) with acceptable r^2^ of 0.773 and 0.863, r^2^~CV~ of 0.752 and 0.775, and r^2^~pred~ of 0.801 and 0.888, respectively, indicating binding activity strongly depends on thermodynamic properties as expressed by the hydrophobicity of molecules.
Highlights
Traditional computer-assisted quantitative structure–activity relationship (QSAR) studies pioneered by Hansch et al (1962) provide a rational basis to establish the relationship between physiochemical properties and biological activity of molecules for better understanding the mechanisms of biological performance and show how to improve performance by altering chemical structures of ligands, which increase the probability of success and reduce the time and cost involved in the modern drug discovery process (Neaz et al, 2008)
The number of descriptors necessary and adequate in the genetic function approximation (GFA)-derived QSAR equations was investigated in the beginning
On the basis of present study, it has been concluded that the described 2D-QSAR analysis contributes to the identification of important physiochemical parameters in explaining the variation in activity in a set of 43 molecules
Summary
Prolonged activation of the host defense human complement system of plasma proteinsSome non-peptide C5a receptor antagonists contributes significantly to amplifying the inflammatory and cellular responses to stimuli such as infectious microorganisms, chemical and physical injury, radiation, or neoplasia (Lama et al, 1992; Finch et al, 1999), resulting in a cascade of proteolytic cleavages of complement proteins Cl-C5 (Vlattas et al, 1994; Wong et al, 1998), assembly of the membrane attack complex capable of cell lysis (Lama et al, 1992) and release of numerous complement-derived peptides of the anaphylatoxins of C3a, C4a and C5a that interact with cellular components to propagate the inflammatory process (Lama et al, 1992; Vlattas et al, 1994). C5a, a 74-amino acid peptide cleaved from C5 at sites of inflammation or infection during activation of the complement system (CS) (Blagg et al, 2008a, 2008b), is a broad pro-inflammatory molecule that binds to G protein-coupled receptors CD88 (C5aR) (Schnatbaum et al, 2006; Barbay et al, 2008) It has been recognized as a very potent inflammatory mediator generated during complement activation (Wong et al, 1998) and a causative or aggravating agent in a variety of inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, immune complex disease, reperfusion injury, Alzheimer’s disease, ischemic heart disease, and adult respiratory distress syndrome (ARDS) (Vlattas et al, 1994; Wong et al, 1998; Finch et al, 1999; Haas et al, 2005). It is necessary and urgent to further understand the C5a structural features important for receptor binding and activation (Vlattas et al, 1994; Finch et al, 1997)
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