A quantitative structure-activity relationship analysis of some 4-aminodiphenyl sulfone antibacterial agents using linear free energy and molecular modeling methods

A set of 36 congeneric 4-aminodiphenyl sulfones with measured inhibition potencies of dihydropteroate synthase were studied by using both linear free energy and molecular modeling methods. The goals of the investigation were to identify the "active" conformation for these compounds as inhibitors and, correspondingly, to contruct a quantitative structure-activity relationship (QSAR). These molecules are quite flexible and possess multiple conformational energy minima. Application of molecular shape analysis (MSA), using all intramolecular energy minima as part of the analysis, was not successful in generating a QSAR. However, the calculated intramolecular conformational entropy of these compounds was found to correlate with inhibition potency leading to a highly significant QSAR. Inhibition potency increases as entropy decreases. A decrease in entropy enhances the population of specific, symmetry-related minimum-energy conformations. In this indirect way, it was possible to postulate an "active" conformation. This investigation illustrates that specific knowledge of the "active" shape of a molecule may not provide the information needed to quantitatively explain the observed structure-activity relationship.     

Transition-state alkylation geometries of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene enantiomeric isomers with nucleic acid dimers

The steric contact spaces associated with the reaction of the enantiomeric isomers of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (I) with the exocyclic amino group of guanine of dinucleoside dimer structures were examined for a fixed transition-state geometry. This reaction is sterically prohibited for the B form DNA conformation. If, however, the nucleic acid structure is deformed, such that the distance between two adjacent base pairs (one containing guanine and cytosine) is maximized, sterically allowed transition-state geometries can be identified. It was not possible to uniquely identify the preferred transition-state complex with respect to nucleic acid structure or isomer of I. However, two types of general transition-state geometries were observed. In one, I was located "outside" the nucleic acid structure; in the other geometry, I was intercalated between adjacent base pairs in the transition state. The intercalation process might serve as a physical catalyst for the alkylation of NH2-guanine by I.     

QSAR analyses of the substituted indanone and benzylpiperidine rings of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase.

QSAR analyses have been performed on the substituted indanone and benzylpiperidine ring substructures of a set of acetylcholinesterase, AChE, inhibitors of which 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride is a potent in vitro and ex vivo inhibitor. The method of molecular decomposition-recomposition was used to define the sets of molecular substructures and corresponding in vitro inhibition databases. A QSAR involving the magnitude of the dipole moment, the highest occupied molecular orbital (HOMO) energy, and a specific pi-orbital wave function coefficient of the substituted indanone ring substructure was constructed and found to be significant. The absence of any molecular-shape or bulk term in the QSAR, coupled with some of the relatively large substituents used to construct the QSAR, suggests considerable space is available around the indanone ring during the inhibition process. A set of QSARs were constructed and evaluated for substituents on the aromatic ring of the benzylpiperidine substructure. The most significant QSAR involves a representation of molecular shape, the largest principal moment of inertia, and the HOMO of the substituted aromatic ring. It appears that upon binding the receptor "wall" is closely fit around the benzyl ring, especially near the para position. Overall, the QSAR analysis suggests inhibition potency can be better enhanced by substitution on the indanone ring, as compared to the aromatic sites of the benzylpiperidine ring. Moreover, inhibition potency can be rapidly diminished, presumably through steric interactions with the receptor surface of AChE, by substitution of moderate to large groups on the benzyl ring, particularly at the para position.     

Top‐down versus bottom‐up attention differentially modulate frontal–parietal connectivity

The moment‐to‐moment focus of our mind's eye results from a complex interplay of voluntary and involuntary influences on attention. Previous neuroimaging studies suggest that the brain networks of voluntary versus involuntary attention can be segregated into a frontal‐versus‐parietal or a dorsal‐versus‐ventral partition—although recent work suggests that the dorsal network may be involved in both bottom‐up and top‐down attention. Research with nonhuman primates has provided evidence that a key distinction between top‐down and bottom‐up attention may be the direction of connectivity between frontal and parietal areas. Whereas typical fMRI connectivity analyses cannot disambiguate the direction of connections, dynamic causal modeling (DCM) can model directionality. Using DCM, we provide new evidence that directed connections within the dorsal attention network are differentially modulated for voluntary versus involuntary attention. These results suggest that the intraparietal sulcus exerts a baseline inhibitory effect on the frontal eye fields that is strengthened during exogenous orienting and attenuated during endogenous orienting. Furthermore, the attenuation from endogenous attention occurs even with salient peripheral cues when those cues are known to be counter predictive. Thus, directed connectivity between frontal and parietal regions of the dorsal attention network is highly influenced by the type of attention that is engaged.     

4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor

A training set of 27 propofol (2,6-diisopropylphenol) analogues was used to construct four-dimensional (4D) quantitative structure-activity relationship (QSAR) models for three screens of biological activity: loss of righting reflex (LORR) in tadpoles, enhancement of agonist activity at the gamma-aminobutyric acid type A (GABA(A)) receptor, and direct (agonist-independent) activation of the receptor. The three resulting 4D-QSAR models are almost identical in form, and all suggest three key ligand-receptor interaction sites. The formation of an intermolecular hydrogen bond involving the proton of the ligand -OH group is the most important binding interaction. A hydrophobic pocket binding interaction involving the six-substituent is the second most significant binding site, and a similar hydrophobic pocket binding interaction near the two-substituent is the third postulated binding site from the 4D-QSAR models. A test set of eight compounds was used to evaluate the tadpole LORR 4D-QSAR model. Those compounds highly congeneric to the training set compounds were accurately predicted. However, compounds exploring substituent sites and/or electronic structures different from the training set were less well-predicted. Overall, the results show a striking similarity between the models of the sites responsible for anesthesia and those mediating effects of the training set of propofol analogues on the GABA(A) receptor; it follows that the GABA(A) receptor is therefore the likely site of propofol's anesthetic action.     

Automatic versus contingent mechanisms of sensory-driven neural biasing and reflexive attention

Recent studies have generated debate regarding whether reflexive attention mechanisms are triggered in a purely automatic stimulus-driven manner. Behavioral studies have found that a nonpredictive "cue" stimulus will speed manual responses to subsequent targets at the same location, but only if that cue is congruent with actively maintained top-down settings for target detection. When a cue is incongruent with top-down settings, response times are unaffected, and this has been taken as evidence that reflexive attention mechanisms were never engaged in those conditions. However, manual response times may mask effects on earlier stages of processing. Here, we used event-related potentials to investigate the interaction of bottom-up sensory-driven mechanisms and top-down control settings at multiple stages of processing in the brain. Our results dissociate sensory-driven mechanisms that automatically bias early stages of visual processing from later mechanisms that are contingent on top-down control. An early enhancement of target processing in the extrastriate visual cortex (i.e., the P1 component) was triggered by the appearance of a unique bright cue, regardless of top-down settings. The enhancement of visual processing was prolonged, however, when the cue was congruent with top-down settings. Later processing in posterior temporal-parietal regions (i.e., the ipsilateral invalid negativity) was triggered automatically when the cue consisted of the abrupt appearance of a single new object. However, in cases where more than a single object appeared during the cue display, this stage of processing was contingent on top-down control. These findings provide evidence that visual information processing is biased at multiple levels in the brain, and the results distinguish automatically triggered sensory-driven mechanisms from those that are contingent on top-down control settings.