Limits...
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

Representation of the residual-QSAR algorithm from a given computed activity (Y0) to the observed one (A) through the "diffracting" process of the residual A-Y0 activity.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3141620&req=5

Figure 1: Representation of the residual-QSAR algorithm from a given computed activity (Y0) to the observed one (A) through the "diffracting" process of the residual A-Y0 activity.

Mentions: This model illustrates the residual QSAR method to amplify asymptotically the computed toxicity towards the observed carcinogenicity (Figure 1). This considers the limitation of no use when considering the case of b1 → 1, which produces the asymptotic (infinite) expressed activity YA→ ∞ with residual correlation. This difficult computation can be removed by reconsidering the residual equation (2) within different computational activity frameworks that are suited to assess the carcinogenic molecular mechanisms.


Residual-QSAR. Implications for genotoxic carcinogenesis.

Putz MV - Chem Cent J (2011)

Representation of the residual-QSAR algorithm from a given computed activity (Y0) to the observed one (A) through the "diffracting" process of the residual A-Y0 activity.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Representation of the residual-QSAR algorithm from a given computed activity (Y0) to the observed one (A) through the "diffracting" process of the residual A-Y0 activity.
Mentions: This model illustrates the residual QSAR method to amplify asymptotically the computed toxicity towards the observed carcinogenicity (Figure 1). This considers the limitation of no use when considering the case of b1 → 1, which produces the asymptotic (infinite) expressed activity YA→ ∞ with residual correlation. This difficult computation can be removed by reconsidering the residual equation (2) within different computational activity frameworks that are suited to assess the carcinogenic molecular mechanisms.

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