Bono Lučić

SAR and QSAR of the Antioxidant Activity of Flavonoids

Flavonoids are a group of naturally occurring phytochemicals abundantly present in fruits, vegetables, and beverages such as wine and tea. In the past two decades, flavonoids have gained enormous interest because of their beneficial health effects such as anti-inflammatory, cardio-protective and anticancer activities. These findings have contributed to the dramatic increase in the consumption and use of dietary supplements containing high concentrations of plant flavonoids. The pharmacological effect of flavonoids is mainly due to their antioxidant activity and their inhibition of certain enzymes. In spite of abundant data, structural requirements and mechanisms underlying these effects have not been fully understood. This review presents the current knowledge about structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs) of the antioxidant activity of flavonoids. SAR and QSAR can provide useful tools for revealing the nature of flavonoid antioxidant action. They may also help in the design of new and efficient flavonoids, which could be used as potential therapeutic agents.

Multivariate Regression Outperforms Several Robust Architectures of Neural Networks in QSAR Modeling

In the past decade, many authors replaced multivariate regression (MR) by the neural networks (NNs) algorithm because they believed the latter to be superior. To verify this, we have undertaken a comparative investigation of the relationship between biological activities and substituent constants representing physicochemical parameters of the substituent groups of 37 carboquinones and 57 benzodiazepines using MR and NNs. A new method for the selection of descriptors in the best possible MR models is presented. The use of orthogonalization procedure makes the calculation of the statistical parameters (e.g. correlation coefficient, R) for each model much simpler, and the selection of the best MR models is accelerated. Such a procedure is applicable to QSAR modeling even for the selection of the best MR model with six descriptors from a set of 100 descriptors. In case one wants to select, for example, the best 15 out of 100 descriptors, a new procedure is developed for the stepwise selection of descriptors i...

Reliability of bond dissociation enthalpy calculated by the PM6 method and experimental TEAC values in antiradical QSAR of flavonoids

The applicability of the newly developed RM1 and PM6 methods implemented in the semiempirical quantum chemistry mopac2009 software package in modeling free radical scavenging activity of flavonoids was examined. Bond dissociation enthalpy (BDE) of OH groups could be calculated much faster than with DFT method but with similar quality. Despite the known shortcomings of the Trolox equivalent antioxidant capacity (TEAC) assay, we show that taking into account the hydrogen atom transfer (HAT) mechanism of free radical scavenging of flavonoids encoded by minimal BDE values (BDE(min)) and the number of OH groups (nOH), as well as experimental data, reasonable QSAR models could be developed. For TEAC values of 38 flavonoids measured by the ABTS free radical, a model based on BDE(min) and nOH was developed, having very good statistical parameters (r=0.983, r(cv)=0.976). The applicability of this model to three different data sets of flavonoids and reliability of TEAC values measured in distinct laboratories were discussed. Finally, a reasonably good model of experimental vitamin C equivalent antioxidant capacity (VCEAC) of 36 flavonoids was obtained (r=0.954, r(cv)=0.947), involving BDE(min) and nOH as descriptors. Additionally, all presented models have comparable fit and cross-validated statistical parameters, as well as significant regression coefficients.

THE VERTEX-CONNECTIVITY INDEX REVISITED

We report a search for optimum molecular descriptors based on the connectivity index. A suggestion made by several authors that the exponent -0.5 used in the standard formula for computing the connectivity index may not be the optimum for modeling some molecular properties was reexamined. We considered several molecular properties and found that in most cases the optimum value of the exponent is indeed different from -0.5. We suggest that a modified version of the (valence) vertex-connectivity index should be routinely employed in the structure-property modeling instead of the standard version of the index.

PM6 and DFT study of free radical scavenging activity of morin

Flavonoids have long been recognised for their general health-promoting properties, of which their antioxidant activity may play an important role. In this work, we have studied the properties of flavonoid morin using semiempirical and density functional theory (DFT) methods in order to validate the application of the recently developed parametric method 6 (PM6). Reaction enthalpies related to mechanisms of free radical scavenging by flavonoid morin were calculated by DFT and PM6 methods in gas-phase, water, DMSO and benzene. It has been shown that fast semiempirical PM6 method can mimic results obtained by means of more accurate time consuming DFT calculations. Thermodynamically favoured mechanism depends on reaction medium: SPLET (sequential proton loss electron transfer) is preferred in water and DMSO, and HAT (hydrogen atom transfer) is predominant in gas-phase. In benzene these two mechanisms are competitive.

Bond dissociation free energy as a general parameter for flavonoid radical scavenging activity

Notwithstanding multiple mechanisms of radical scavenging (RS), measured RS activities (RSA) of flavonoids are usually related to O-H bond dissociation enthalpy (BDE) for hydrogen atom transfer (HAT). For 12 flavonoids the reaction free energies were calculated for: (1) HAT, (2) single electron transfer-proton transfer (SET-PT) and (3) sequential proton loss electron transfer (SPLET) in gas and aqueous phases. Aqueous free energies, like bond dissociation (BDFEaq), ionisation (IFEaq) and deprotonation (ΔGdeprot,aq) free energies were estimated using thermochemical cycles. While in gas HAT is a RS mechanism (BDFEg<IFEg<ΔGdeprot,g), in water SPLET can be concurrent or dominant mechanism depending upon pH since ΔGdeprot,aq<BDFEaq and ETFEaq⩽BDFEaq. For 12 flavonoids, BDFEaq has been correlated with ΔGdeprot,aq and ETFEaq with r=0.74 and 0.87 respectively. This reveals why BD(F)E parameter explains most of variance in variously measured RSA data even if the underlying mechanism is SPLET.

The Detour Matrix in Chemistry

The detour matrix of a (chemical) graph is defined. The detour matrix is also defined for weighted graphs. A novel method of computing the detour matrix is introduced. Some properties of the detour matrix and the distance matrix are compared. The invariants of the detour matrix (detour polynomial, detour spectrum, and detour index) are discussed, and several methods for computing these quantities are presented. The use of the detour index is analyzed and compared to the application of the Wiener number in the structure−boiling point modeling.

Towards an improved prediction of the free radical scavenging potency of flavonoids: the significance of double PCET mechanisms.

The 1H(+)/1e(-) and 2H(+)/2e(-) proton-coupled electron transfer (PCET) processes of free radical scavenging by flavonoids were theoretically studied for aqueous and lipid environments using the PM6 and PM7 methods. The results reported here indicate that the significant contribution of the second PCET mechanism, resulting in the formation of a quinone/quinone methide, effectively discriminates the active from inactive flavonoids. The predictive potency of descriptors related to the energetics of second PCET mechanisms (the second O-H bond dissociation enthalpy (BDE2) related to hydrogen atom transfer (HAT) mechanism, and the second electron transfer enthalpy (ETE2) related to sequential proton loss electron transfer (SPLET) mechanism) are superior to the currently used indices, which are related to the first 1H(+)/1e(-) processes, and could serve as primary descriptors in development of the QSAR (quantitative structure-activity relationships) of flavonoids.

Knowledge-based computational methods for identifying or designing novel, non-homologous antimicrobial peptides

We describe computational approaches for identifying promising lead candidates for the development of peptide antibiotics, in the context of quantitative structure–activity relationships (QSAR) studies for this type of molecule. A first approach deals with predicting the selectivity properties of generated antimicrobial peptide sequences in terms of measured therapeutic indices (TI) for known antimicrobial peptides (AMPs). Based on a training set of anuran AMPs, the concept of sequence moments was used to construct algorithms that could predict TIs for a second test set of natural AMPs and could also predict the effect of point mutations on TI values. This approach was then used to design peptide antibiotics (adepantins) not homologous to known natural or synthetic AMPs. In a second approach, many novel putative AMPs were identified from DNA sequences in EST databases, using the observation that, as a rule, specific subclasses of highly conserved signal peptides are associated exclusively with AMPs. Both anuran and teleost sequences were used to elucidate this observation and its implications. The predicted therapeutic indices of identified sequences could then be used to identify new types of selective putative AMPs for future experimental verification.

PM6 study of free radical scavenging mechanisms of flavonoids: why does O–H bond dissociation enthalpy effectively represent free radical scavenging activity?

AbstractIt is well known that the bond dissociation enthalpy (BDE) of the O–H group is related to the hydrogen atom transfer (HAT) mechanism of free radical scavenging that is preferred in gas-phase and non-polar solvents. The present work shows that the BDE may also be related to radical scavenging processes taking place in polar solvents, i.e., single electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). This is so because the total energy requirements related to the SET-PT [sum of the ionization potential (IP) and proton dissociation enthalpy (PDE)] and the SPLET [sum of the proton affinity (PA) and electron transfer enthalpy (ETE)] are perfectly correlated with the BDE. This could explain why the published data for polyphenolic antioxidant activity measured by various assays are better correlated with the BDE than with other reaction enthalpies involved in radical scavenging mechanisms, i.e., the IP, PDE, PA and ETE. The BDE is fairly well able to rank flavonoids as antioxidants in any medium, but to conclude which radical scavenging mechanism represents the most probable reaction pathway from the thermodynamic point of view, the IP and PA (ETE) should also be considered. This is exemplified in the case of the radical scavenging activity of 25 flavonoids. FigureTotal energy requirements related to the SET-PT and SPLET mechanisms are equivalent to those of the HAT mechanism and are correlated perfectly with the BDE values.