Direct SN2 or SN2X Manifold – Mechanistic Study of Ion-Pair Catalyzed Carbon(sp3)-Carbon(sp3) Bond Formation

Density functional theory (DFT) is used in this work to predict the mechanism for constructing congested quaternary-quaternary carbon(sp3)–carbon(sp3) bonds in a pentanidium catalyzed substitution reaction. Computational mechanistic studies were carried out to investigate the proposed SN2X manifold, which consists of two primary elementary steps: halogen atom transfer (XAT) and subsequent SN2. For the first calculated model on original experimental substrates, XAT reaction barriers were more kinetically competitive than an SN2 pathway and connects to thermodynamically stable intermediates. Extensive computational screening-modelling were then done on various substrate combinations designed to study steric influence and to understand the mechanistic rationale, and calculations reveal that sterically congested substrates prefer the SN2X manifold over SN2. Different halides as leaving groups were also screened and it was found that the reactivity increases in order of Br > Cl > F in agreement of the strength of C–X bonds. However, DFT modelling suggests that chlorides can be a viable substrate for the SN2X process which should be further explored experimentally. Finally, ONIOM calculations on the full catalyst model were carried out to rationalize the stereoselectivity which corroborates with experimental results.

MDO: A Computational Protocol for Accurate Prediction of Full Flexibility Receptor-Ligand Binding Mode Structures

Predicting the binding structure of bio-complex is essential for understanding its properties, functions, and mechanisms, but is rather difficult due to the huge sampling space involved. A new computational protocol, MDO, for finding the ligand binding structure is proposed. MDO consists of global sampling via MD simulation and clustering of the receptor configurations, local sampling via molecular docking and clustering of the ligand conformations, and binding structure optimization by the ONIOM (QM/QM) method. MDO is tested on 15 protein-ligand complexes with known accurate structures. The success rate of MDO predictions, with RMSD < 2 Å, is found to be 67%, substantially higher than the 40% success rate of conventional methods. The MDO success rate can be increased to 83% if the ONIOM calculations are applied only for the starting poses with ligands inside the binding cavities. The MDO protocol is a promising tool for the structure based drug design.

Insights from QM/MM-ONIOM calculations: the TADF phenomenon of phenanthro[9,10-d]imidazole-anthraquinone in the solid state

The QM/MM technique is employed to study the TADF phenomenon of a near-infrared molecule (PIPAQ) in aggregation state, the calculated results can prove the steric hindrance effect from the surrounding molecules.

Strong inhibition of M-Protease activity of Coronavirus by using PX-12 inhibitor based on ab initio ONIOM calculations

In this study, the interaction of seven potential inhibitors in complex with SARS-CoV-2’s M protease (Mpro) is modelled and optimized using ONIOM (Own N-layered Integrated molecular Orbital and molecular Mechanics; QM/MM) approach. Density functional theory is used for the small system and Universal Force Field is used for the rest of the molecule with ONIOM (m062x/6-311++G (d,p):UFF) model chemistry. The seven inhibitors that are used in this study are N3, ebselen, disulfiram, tideglusib, carmofur, shikonin and PX-12. The calculated interaction energy between the inhibitor and Mpro shows a strong inhibition of Mpro activity with N3, ebselen as well as PX-12 inhibitors. The two former inhibitors are previously reported as strong inhibitors; however, the strong inhibition effect of PX-12 has not been previously reported. The results of this study can provide useful insight into designing an effective inhibitor drug for SARS-nCoV, suggesting a better inhibition from PX-12 than ebselen.