Molecular Docking and Dynamics Investigations for Identifying Potential Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2: Repurposing of Approved Pyrimidonic Pharmaceuticals for COVID-19 Treatment

This study demonstrates the inhibitory effect of 42 pyrimidonic pharmaceuticals (PPs) on the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) through molecular docking, molecular dynamics simulations, and free binding energies by means of molecular mechanics–Poisson Boltzmann surface area (MM-PBSA) and molecular mechanics–generalized Born surface area (MM-GBSA). Of these tested PPs, 11 drugs approved by the US Food and Drug Administration showed an excellent binding affinity to the catalytic residues of 3CLpro of His41 and Cys145: uracil mustard, cytarabine, floxuridine, trifluridine, stavudine, lamivudine, zalcitabine, telbivudine, tipiracil, citicoline, and uridine triacetate. Their percentage of residues involved in binding at the active sites ranged from 56 to 100, and their binding affinities were in the range from −4.6 ± 0.14 to −7.0 ± 0.19 kcal/mol. The molecular dynamics as determined by a 200 ns simulation run of solvated docked complexes confirmed the stability of PP conformations that bound to the catalytic dyad and the active sites of 3CLpro. The free energy of binding also demonstrates the stability of the PP–3CLpro complexes. Citicoline and uridine triacetate showed free binding energies of −25.53 and −7.07 kcal/mol, respectively. Therefore, I recommend that they be repurposed for the fight against COVID-19, following proper experimental and clinical validation.

The Omicron Variant Increases the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2

The Omicron variant (B.1.1.529) comprises 30 mutations on the spike glycoprotein (S), 15 of which are located on its receptor-binding domain (RBD_Omicron). RBD interacts with the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors and plays a critical role in the host cell entry of the virus. We performed all-atom simulations of the RBD_Omicron-PD in the presence of explicit water and ions. Simulations showed a considerably more extensive interactions network between RBD_Omicron and PD compared to RBD_WT, comprising a 250%, 10% and -25% change in the total number of salt bridges, hydrophobic interactions, hydrogen bonds at the S-ACE2 interface, respectively. Using the conformations sampled in each our MD trajectories, binding energies of two sets of RBD_WT-PD and four sets of RBD_Omicron-PD simulations were calculated via the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method, estimating ~44% stronger binding energy for RBD_Omicron compared to RBD_WT. Our results suggest that an increase in the number of salt bridges in the S-ACE2 interface result in a higher binding strength of RBD to PD, which may result in a higher efficiency of the SARS-CoV-2 virus to infect host cells. Furthermore, RBD_Omicron exhibits a more dispersed interaction network on both sides of the RBD-PD interaction surface compared to WT.

Fe and Ag supported on activated carbon as an effective adsorbent for 2,4-dichlorophenoxylacetic acid treatment: a theoretical study

Extended tight-binding quantum chemical method (GFN2-xTB) was performed to investigate the adsorption of 2,4-dichlorophenoxylacetic acid (2,4-D) on activated carbon (AC) and AC modified by Fe or Ag (AC-M). Electronic properties of the studied systems were estimated via vertical ionisation potential, vertical electron affinity, and global electrophilicity index. Adsorption energy, population analysis, and geometrical parameters were calculated to clarify the adsorption ability of AC and AC-M. The results indicated that the introduction of metal atoms to AC substantially enhanced the adsorption ability for 2,4-D. The adsorption mechanism changed from physical adsorption (on AC) to chemisorption (on AC-M). The influence of different solvents (water, methanol, and acetonitrile) on the adsorption process was studied via an Analytical linearized Poisson-Boltzmann algorithm.

Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome

Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.

Evaluation on the performance of MM/PBSA in nucleic acid-protein systems

The molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method has been widely used in predicting the binding affinity among the ligands, the proteins and the nucleic acids. However, the accuracy of the predicted binding energy by the standard MM/PBSA is not always good, especially in highly charged systems. In this work, we take the protein-nucleic acid complexes as an example, and showed that the use of screening electrostatic energy (instead of coulomb electrostatic energy) in molecular mechanics can greatly improve the performance of MM/PBSA. In particular, the Pearson correlation coefficient of dataset II in the modified MM/PBSA (i.e., screening MM/PBSA) is about 0.52, much better than that (<0.33) in the standard MM/PBSA. Further, we also evaluate the effect of the solute dielectric constant and the salt concentration on the performance of the screening MM/PBSA. The present study highlights the potential power of the screening MM/PBSA for predicting the binding energy in highly charged bio-systems.

Ionization equilibrium in a highly imperfect smoke plasma

The ionization equilibrium in a heterogeneous strongly nonideal smoky plasmas containing condensed particles and an easily ionized addition of cesium atoms in the gas phase is considered. To determine the charges of particles, the nonlinear Poisson-Boltzmann equation was used, and for the ionization of atoms of the gas phase, the Saha equation taking into account the effect of the displacement of the ionization equilibrium. The dependences of the concentration of electrons and particle charges, as well as the interface between the regions of positive and negative charges of particles, on the concentration of cesium atoms and the concentration of aluminum oxide particles are obtained.