We have quantum chemically analyzed the competition between the bimolecular nucleophilic substitution (S N 2) and base-induced elimination (E2) pathways for F – + CH 3 CH 2 Cl and PH 2 – + CH 3 CH 2 Cl using the activation strain model and Kohn–Sham molecular orbital theory at ZORA-OLYP/QZ4P. Herein, we correct an earlier study that intuitively attributed the mechanistic preferences of F – and PH 2 – , i.e., E2 and S N 2, respectively, to a supposedly unfavorable shift in the polarity of the abstracted β-proton along the PH 2 – -induced E2 pathway while claiming that ″ ...no correlation between the thermodynamic basicity and E2 rate should be expected. ″ Our analyses, however, unequivocally show that it is simply the 6 kcal mol –1 higher proton affinity of F – that enables this base to engage in a more stabilizing orbital interaction with CH 3 CH 2 Cl and hence to preferentially react via the E2 pathway, despite the higher characteristic distortivity (more destabilizing activation strain) associated with this pathway. On the other hand, the less basic PH 2 – has a weaker stabilizing interaction with CH 3 CH 2 Cl and is, therefore, unable to overcome the characteristic distortivity of the E2 pathway. Therefore, the mechanistic preference of PH 2 – is steered to the S N 2 reaction channel (less-destabilizing activation strain).

We have quantum chemically investigated the bonding between archetypical Lewis acids and bases. Our state-of-the-art computations on the X 3 BÀ NY 3 Lewis pairs have revealed the origin behind the systematic increase in BÀ N bond strength as X and Y are varied from F to Cl, Br, I, H. For H 3 BÀ NY 3 , the bonding trend is driven by the commonly accepted mechanism of donorÀ acceptor [HOMO (base)À LUMO(acid)] interaction. Interestingly, for X 3 BÀ NH 3 , the bonding mechanism is determined by the energy required to deform the BX 3 to the pyramidal geometry it adopts in the adduct. Thus, Lewis acids that can more easily pyramidalize form stronger bonds with Lewis bases. The decrease in the strain energy of pyramidalization on going from BF 3 to BI 3 is directly caused by the weakening of the BÀ X bond strength, which stems primarily from the bonding in the plane of the molecule (σ-like) and not in the π system, at variance with the currently accepted mechanism.

This Point/Counterpoint article addresses a long-standing but still-unresolved debate on the advantages and disadvantages of using live patients in dental licensure exams. Two contrasting viewpoints are presented. Viewpoint 1 supports the traditional use of live patients, arguing that other assessment models have not yet been demonstrated to be viable alternatives to the actual treatment of patients in the clinical licensure process. This viewpoint also contends that the use of live patients and inherent variances in live patient treatment represent the realities of daily private practice. Viewpoint 2 argues that the use of live patients in licensure exams needs to be discontinued considering those exams' ethical dilemmas of exposing patients to potential harm, as well as their lack of reliability and validity and limited scope. According to this viewpoint, the current presence of viable alternatives means that the risk of harm inherent in live patient exams can finally be eliminated and those exams replaced with other means to confirm that candidates are qualified for licensure to practice.

Some nitrile-boron halide adducts exhibit a double-well potential energy surface with two distinct minima: a "long bond" geometry (LB, a van der Waals interaction mostly based on electrostatics, but including a residual charge transfer component) and a "short bond" structure (SB, a covalent dative bond). This behavior can be considered as a "weak" form of bond stretch isomerism. Our computations reveal that complexes RCNÀ BX 3 (R = CH 3 , FCH 2 , BrCH 2 , and X = Cl, Br) exhibit a fast interconversion from LB to SB geometries even close to the absolute zero thanks to a boron atom tunneling mechanism. The computed half-lives of the meta-stable LB compounds vary between minutes to nanoseconds at cryogenic conditions. Accordingly, we predict that the long bond structures are practically impossible to isolate or characterize, which agrees with previous matrix-isolation experiments.

No abstract

In this study, quantitative structure-activity relationship studies which make use of molecular dynamics trajectories were performed on a set of 54 glucokinase protein activators. The conformations obtained by molecular dynamics simulation were superimposed according to the twelve alignments tested in a virtual three-dimensional box comprised of 2 Å cells. The models were generated by the technique that combines genetic algorithms and partial least squares. The best alignment models generated with a determination coefficient (r(2)) between 0.674 and 0.743 and cross-validation (q(2)) between 0.509 and 0.610, indicating good predictive capacity. The 4D-QSAR models developed in this study suggest novel molecular regions to be explored in the search for better glucokinase activators.

Herein, we have investigated the effect of an endocyclic group (forming the N–C–C–F fragment) on the conformational preferences of 2‐fluorocyclohexanone analogs. A combined approach of nuclear magnetic resonance and density functional theory calculations was employed to assess the conformational equilibrium in several media. In turn, natural bond orbital analysis and the conformational behavior of other 2‐halocyclohexanone analogs were used to get more insights about the intramolecular interactions governing the conformer stabilities. Our results reveal that any stabilization from interactions featured in the gauche effect is overcome by a short‐range interaction of the fluorine substituent with the carbonyl group. Consequently, the gauche effect in heterocyclic compounds is not as stabilizing as in their acyclic counterparts. Only the electrostatic gauche effect takes place even in polar solvents owing to an attraction between the axial fluorine and an endocyclic quaternary ammonium group.

Despite recent advances in Computer Aided Drug Discovery and High Throughput Screening, the attrition rates of drug candidates continue to be high, underscoring the inherent complexity of the drug discovery paradigm. Indeed, a compromise between several objectives is often required to obtain successful clinical drugs. The present manuscript details a multi-objective workflow that integrates the 4D-QSAR and molecular docking methods in the simultaneous modeling of the Rho Kinase inhibitory activity and acute toxicity of Benzamide derivatives. To this end, the pIC /pLD ratio is considered as the response variable, permitting the concurrent modeling of both properties and representing a shift from classical step-by-step evaluations. The 4D-QSAR strategy is used to generate the Grid Cell Occupancy Descriptors (GCODs), and Stochastic Gradient Boosting (SGB) and Partial Least Squares (PLS) methods as the model fitting techniques. While the statistical parameters for the PLS model do not meet established criteria for acceptability, the SGB model yields satisfactory performance, with correlation coefficients r =0.95 and r pred=0.65 for the training and test set, respectively. Posteriorly, the structural interpretation of the most relevant GCODs according to the SGB model is performed, allowing for the proposal of 139 novel benzamide derivatives, which are then screened using the same model. Of these 9 compounds were predicted to possess pIC /pLD ratio values higher than those for the employed dataset. Finally, in order to corroborate the results obtained with the SGB model, a docking simulation was formed to evaluate the binding affinity of the proposed molecules to the ROCK2 active site and 3 chemical structures (i. e. p6, p14 and p131) showed higher binding affinity than the most active compound in the training set, while the rest generally demonstrated comparable behavior. It may therefore be concluded that the consensus models that intertwine the 4D-QSAR and molecular docking methods contribute to more reliable virtual screening and compound optimization experiments. Additionally, the use of multi-objective modeling schemes permits the simultaneous evaluation of different chemical and biological profiles, which should contribute to the control a priori of causative factors for the high attrition rates in later drug discovery phases.