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Residual-QSAR. Implications for genotoxic carcinogenesis.

Putz MV - Chem Cent J (2011)

Bottom Line: A self-consistent equation of observed-computed activity was assumed to give maximum correlation efficiency for those situations in which the direct correlations gave non-significant statistical information.Once defined, the endpoint associated with ligand-DNA interaction was used to select variables that retained the main Hansch physicochemical parameters of hydrophobicity, polarizability and stericity, computed by the custom PM3 semiempirical quantum method.Additionally, it could be extended to enriched physicochemical structural indices by considering the molecular fragments or structural alerts (or other molecular residues), providing more detailed maps of chemical-biological interactions and pathways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Computational and Structural Physical Chemistry, Chemistry Department, West University of Timişoara, Pestalozzi Street No,16, Timişoara, RO-300115, Romania. mv_putz@yahoo.com.

ABSTRACT

Introduction: Both main types of carcinogenesis, genotoxic and epigenetic, were examined in the context of non-congenericity and similarity, respectively, for the structure of ligand molecules, emphasizing the role of quantitative structure-activity relationship ((Q)SAR) studies in accordance with OECD (Organization for Economic and Cooperation Development) regulations. The main purpose of this report involves electrophilic theory and the need for meaningful physicochemical parameters to describe genotoxicity by a general mechanism. RESIDUAL-QSAR METHOD: The double or looping multiple linear correlation was examined by comparing the direct and residual structural information against the observed activity. A self-consistent equation of observed-computed activity was assumed to give maximum correlation efficiency for those situations in which the direct correlations gave non-significant statistical information. Alternatively, it was also suited to describe slow and apparently non-noticeable cancer phenomenology, with special application to non-congeneric molecules involved in genotoxic carcinogenesis.

Application and discussions: The QSAR principles were systematically applied to a given pool of molecules with genotoxic activity in rats to elucidate their carcinogenic mechanisms. Once defined, the endpoint associated with ligand-DNA interaction was used to select variables that retained the main Hansch physicochemical parameters of hydrophobicity, polarizability and stericity, computed by the custom PM3 semiempirical quantum method. The trial and test sets of working molecules were established by implementing the normal Gaussian principle of activities that applies when the applicability domain is not restrained to the congeneric compounds, as in the present study. The application of the residual, self-consistent QSAR method and the factor (or average) method yielded results characterized by extremely high and low correlations, respectively, with the latter resembling the direct activity to parameter QSARs. Nevertheless, such contrasted correlations were further incorporated into the advanced statistical minimum paths principle, which selects the minimum hierarchy from Euclidean distances between all considered QSAR models for all combinations and considered molecular sets (i.e., school and validation). This ultimately led to a mechanistic picture based on the identified alpha, beta and gamma paths connecting structural indicators (i.e., the causes) to the global endpoint, with all included causes. The molecular mechanism preserved the self-consistent feature of the residual QSAR, with each descriptor appearing twice in the course of one cycle of ligand-DNA interaction through inter-and intra-cellular stages.

Conclusions: Both basal features of the residual-QSAR principle of self-consistency and suitability for non-congeneric molecules make it appropriate for conceptually assessing the mechanistic description of genotoxic carcinogenesis. Additionally, it could be extended to enriched physicochemical structural indices by considering the molecular fragments or structural alerts (or other molecular residues), providing more detailed maps of chemical-biological interactions and pathways.

No MeSH data available.


Related in: MedlinePlus

Illustration of the molecular mechanism for genotoxic carcinogenesis according to the present residual-QSAR correlation-path hierarchy superimposed over an immunohistochemcial analysis of paraffin-embedded sections of rat intestinal cancer using the Caspase-2 antibody [42].
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Figure 3: Illustration of the molecular mechanism for genotoxic carcinogenesis according to the present residual-QSAR correlation-path hierarchy superimposed over an immunohistochemcial analysis of paraffin-embedded sections of rat intestinal cancer using the Caspase-2 antibody [42].

Mentions: beginning with the associated scenario (Figure 3[42]). A molecule is first polarized (POL) upon entering intercellular space due to the plasmatic environment's solvent effects. It then rotates to the optimal steric position (Etot) to realize cellular membrane transduction by activating its hydrophobicity (LogP). It may travel this way though the cellular space while binding to DNA elements via further steric interactions (Etot) and while remaining polarized. It may eventually break some parts of DNA residues and carry them in the extra-cellular space (LogP), where the enriched molecule will suffer further polarization (POL) from solvent interactions with the new molecular structure. The mechanism then enters a new ligand-DNA cycle, while the remaining DNA will enter mutagenesis. Remarkably, each considered structural (causal) indicator acted twice at the level of one interaction cycle in the obtained mechanism (17) in accordance with the self-consistent nature of the present residual-QSAR analysis (Eq. (3)).


Residual-QSAR. Implications for genotoxic carcinogenesis.

Putz MV - Chem Cent J (2011)

Illustration of the molecular mechanism for genotoxic carcinogenesis according to the present residual-QSAR correlation-path hierarchy superimposed over an immunohistochemcial analysis of paraffin-embedded sections of rat intestinal cancer using the Caspase-2 antibody [42].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3141620&req=5

Figure 3: Illustration of the molecular mechanism for genotoxic carcinogenesis according to the present residual-QSAR correlation-path hierarchy superimposed over an immunohistochemcial analysis of paraffin-embedded sections of rat intestinal cancer using the Caspase-2 antibody [42].
Mentions: beginning with the associated scenario (Figure 3[42]). A molecule is first polarized (POL) upon entering intercellular space due to the plasmatic environment's solvent effects. It then rotates to the optimal steric position (Etot) to realize cellular membrane transduction by activating its hydrophobicity (LogP). It may travel this way though the cellular space while binding to DNA elements via further steric interactions (Etot) and while remaining polarized. It may eventually break some parts of DNA residues and carry them in the extra-cellular space (LogP), where the enriched molecule will suffer further polarization (POL) from solvent interactions with the new molecular structure. The mechanism then enters a new ligand-DNA cycle, while the remaining DNA will enter mutagenesis. Remarkably, each considered structural (causal) indicator acted twice at the level of one interaction cycle in the obtained mechanism (17) in accordance with the self-consistent nature of the present residual-QSAR analysis (Eq. (3)).

Bottom Line: A self-consistent equation of observed-computed activity was assumed to give maximum correlation efficiency for those situations in which the direct correlations gave non-significant statistical information.Once defined, the endpoint associated with ligand-DNA interaction was used to select variables that retained the main Hansch physicochemical parameters of hydrophobicity, polarizability and stericity, computed by the custom PM3 semiempirical quantum method.Additionally, it could be extended to enriched physicochemical structural indices by considering the molecular fragments or structural alerts (or other molecular residues), providing more detailed maps of chemical-biological interactions and pathways.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Computational and Structural Physical Chemistry, Chemistry Department, West University of Timişoara, Pestalozzi Street No,16, Timişoara, RO-300115, Romania. mv_putz@yahoo.com.

ABSTRACT

Introduction: Both main types of carcinogenesis, genotoxic and epigenetic, were examined in the context of non-congenericity and similarity, respectively, for the structure of ligand molecules, emphasizing the role of quantitative structure-activity relationship ((Q)SAR) studies in accordance with OECD (Organization for Economic and Cooperation Development) regulations. The main purpose of this report involves electrophilic theory and the need for meaningful physicochemical parameters to describe genotoxicity by a general mechanism. RESIDUAL-QSAR METHOD: The double or looping multiple linear correlation was examined by comparing the direct and residual structural information against the observed activity. A self-consistent equation of observed-computed activity was assumed to give maximum correlation efficiency for those situations in which the direct correlations gave non-significant statistical information. Alternatively, it was also suited to describe slow and apparently non-noticeable cancer phenomenology, with special application to non-congeneric molecules involved in genotoxic carcinogenesis.

Application and discussions: The QSAR principles were systematically applied to a given pool of molecules with genotoxic activity in rats to elucidate their carcinogenic mechanisms. Once defined, the endpoint associated with ligand-DNA interaction was used to select variables that retained the main Hansch physicochemical parameters of hydrophobicity, polarizability and stericity, computed by the custom PM3 semiempirical quantum method. The trial and test sets of working molecules were established by implementing the normal Gaussian principle of activities that applies when the applicability domain is not restrained to the congeneric compounds, as in the present study. The application of the residual, self-consistent QSAR method and the factor (or average) method yielded results characterized by extremely high and low correlations, respectively, with the latter resembling the direct activity to parameter QSARs. Nevertheless, such contrasted correlations were further incorporated into the advanced statistical minimum paths principle, which selects the minimum hierarchy from Euclidean distances between all considered QSAR models for all combinations and considered molecular sets (i.e., school and validation). This ultimately led to a mechanistic picture based on the identified alpha, beta and gamma paths connecting structural indicators (i.e., the causes) to the global endpoint, with all included causes. The molecular mechanism preserved the self-consistent feature of the residual QSAR, with each descriptor appearing twice in the course of one cycle of ligand-DNA interaction through inter-and intra-cellular stages.

Conclusions: Both basal features of the residual-QSAR principle of self-consistency and suitability for non-congeneric molecules make it appropriate for conceptually assessing the mechanistic description of genotoxic carcinogenesis. Additionally, it could be extended to enriched physicochemical structural indices by considering the molecular fragments or structural alerts (or other molecular residues), providing more detailed maps of chemical-biological interactions and pathways.

No MeSH data available.


Related in: MedlinePlus