Dissociation Mode of the O-H Bond in Betanidin, pKa-Clusterization Prediction, and Molecular Interactions via Shape Theory and DFT Methods.

Betanidin (Bd) is a nitrogenous metabolite with significant bioactive potential influenced by pH. Its free radical scavenging activity and deprotonation pathway are crucial to studying its physicochemical properties. Motivated by the published discrepancies about the best deprotonation routes in Bd, this work explores all possible pathways for proton extractions on that molecule, by using the direct approach method based on pKa. The complete space of exploration is supported by a linear relation with constant slope, where the pKa is written in terms of the associated deprotonated molecule energy. The deprotonation rounds 1, …, 6 define groups of parallel linear models with constant slope. The intercepts of the models just depend on the protonated energy for each round, and then the pKa can be trivially ordered and explained by the energy. We use the direct approximation method to obtain the value of pKa. We predict all possible outcomes based on a linear model of the energy and some related verified assumptions. We also include a new measure of similarity or dissimilarity between the protonated and deprotonated molecules, via a geometric-chemical descriptor called the Riemann-Mulliken distance (RMD). The RMD considers the cartesian coordinates of the atoms, the atomic mass, and the Mulliken charges. After exploring the complete set of permutations, we show that the successive deprotonation process does not inherit the local energy minimum and that the commutativity of the paths does not hold either. The resulting clusterization of pKa can be explained by the local acid and basic groups of the BD, and the successive deprotonation can be predicted by using the chemical explained linear models, which can avoid unnecessary optimizations. Another part of the research uses our own algorithm based on shape theory to determine the protein's active site automatically, and molecular dynamics confirmed the results of the molecular docking of Bd in protonated and anionic form with the enzyme aldose reductase (AR). Also, we calculate the descriptors associated with the SET and SPLET mechanisms.

Shape Theory Applied to Molecular Docking and Automatic Localization of Ligand Binding Pockets in Large Proteins.

Automatic search of cavities and binding mode analysis between a ligand and a 3D protein receptor are challenging problems in drug design or repositioning. We propose a solution based on a shape theory theorem for an invariant coupled system of ligand-protein. The theorem provides a matrix representation with the exact formulas to be implemented in an algorithm. The method involves the following results: (1) exact formulae for the shape coordinates of a located-rotated invariant coupled system; (2) a parameterized search based on a suitable domain of van der Waals radii; (3) a scoring function for the discrimination of sites by measuring the distance between two invariant coupled systems including the atomic mass; (4) a matrix representation of the Lennard-Jones potential type 6-12 and 6-10 as the punctuation function of the algorithm for a molecular docking; and (5) the optimal molecular docking as a solution of an optimization problem based on the exploration of an exhaustive set of rotations. We apply the method in the xanthine oxidase protein with the following ligands: hypoxanthine, febuxostat, and chlorogenic acid. The results show automatic cavity detection and molecular docking not assisted by experts with meaningful amino acid interactions. The method finds better affinities than the expert software for known published cavities.

Screening for conduct disorder in an adolescent male sample from Colombia.

This study assessed the validity, reliability, and utility of a screening measure for detecting the signs or symptoms of Conduct Disorder in male adolescents from schools in Medellín, Colombia. A first study examined the differences between 70 male offender adolescents (aged 12-16 years) attending alternative education institutions, and 68 (sex, age, and socioeconomic status (SES)-matched) adolescent controls attending regular schools. A CD checklist (CD-CL) was constructed to be used by mothers (CD-CL-M) and for self-report by adolescents (CD-CL-SR). The validity of the screener for CD diagnosis was supported by significant differences between groups (ANOVA, p<.001). The CD-CL-SR had better sensitivity/specificity with a diagnostic cut-off point of 5 (sensitivity=95.3% and specificity=90.5%) than the CD-CL-M. A second study used the CD-CLSR with a random sample of 190 male adolescents (aged 12 to 16 years) from schools of low, middle and high SES. Reliability as assessed by Cronbach's alpha was 0.86. An epidemiological cut point of 5 classified 35.5% of the adolescents assessed as probable CD cases. A psychometric cut point at T score>59 (85th percentile) estimated 16.8% of the sample as probable CD cases. A psychometric cut point at T score>64 (90th percentile) revealed that 10.5% of the sample would be severe CD cases. Some significant differences (p<0.001) in proportions of CD adolescents were found between age and SES groups. It was concluded that such a high frequency of conduct problems in adolescence argues for the need for preventive programs in Colombian schools.

Validation of two rating scales for attention-deficit hyperactivity disorder diagnosis in Colombian children.

This study assesses the validity of the Behavioral Assessment System for Children-parent and teacher questionnaires for attention-deficit hyperactivity disorder diagnosis in a randomized sample of 344 Colombian children (145 cases, 199 controls), males and females, ages 6 to 11, with an estimated Wechsler Full Scale Intelligence Quotient over 70. The assessment protocol for both groups included psychiatric, neurologic, and psychological interviews, parent and teacher rating forms, and an Attention-Deficit Hyperactivity Disorder Checklist. All Behavioral Assessment System for Children-parent and teacher dimensions, except withdrawal and somatization, significantly differentiated cases and controls. Parents and teachers rated attention-deficit hyperactivity disorder combined type children as significantly more aggressive. Both questionnaires had good discriminant accuracy for detecting cases and control children, but accuracy for discriminating between attention-deficit hyperactivity disorder subtypes was poor. The Behavioral Assessment System for Children-parent and teacher questionnaires for 6- to 11-year-olds may be useful tools for diagnosing the presence of attention-deficit hyperactivity disorder. Additional assessment methods will be needed to discriminate between the subtypes.