In Silico Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-Like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17, 28, 31, 40, 41, 43, 47, 54, and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28, 34, and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28, 34, and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).

Charge density view on bicalutamide molecular interactions in the monoclinic polymorph and androgen receptor binding pocket

High-resolution single-crystal X-ray measurements of the monoclinic polymorph of bicalutamide and the aspherical atom databank approach have served as a basis for a reconstruction of the charge density distribution of the drug and its androgen receptor (AR) and albumin complexes. The contributions of various types of intermolecular interactions to the total crystal energy or ligand:AR energy were estimated. The cyan and amide groups secured the ligand placement in the albumin (Lys-137) and the AR binding pocket (Leu-704, Asn-705, Arg-752), and also determined the packing of the small-molecule crystals. The total electrostatic interaction energy on average was −230 kJ mol−1, comparable with the electrostatic lattice energy of the monoclinic bicalutamide polymorph. This is the result of similar distributions of electropositive and electronegative regions on the experimental and theoretical molecular electrostatic potential maps despite differences in molecular conformations. In general, bicalutamide interacted with the studied proteins with similar electrostatic interaction energies and adjusted its conformation and electrostatic potential to fit the binding pocket in such a way as to enhance the interactions, e.g. hydrogen bonds and π...π stacking.

Physico-chemical characterization of hybridized graphene and boron-nitride layers

<p>New materials can be created by modifying matter. In this work we characterize graphene and boron-nitride (BN) layers after doping them with BN and carbon dimers, respectively, in different amounts and with different spatial distributions. We provide the energetic description, electron density features, molecular electrostatic potential maps, net charge populations, and the speeds of propagating waves on the hybridized layers. We show the possibility of designing molecular electrostatic potentials from a spatially controlled doping. A strategy is illustrated on a BN hybrid layer with the adsorption of DNA nucleic acid bases.</p>

Physico-chemical characterization of hybridized graphene and boron-nitride layers

New materials can be created by modifying matter. In this work, we characterize graphene and boronnitride (BN) layers after doping them with BN and carbon dimers, respectively, in different amounts and with different spatial distributions. We provide the energetic description, electron density features, molecular electrostatic potential maps, net charge populations, and the speeds of propagating waves on the hybridized layers. We show the possibility of designing molecular electrostatic potentials from a spatially controlled doping. A strategy is illustrated on a BN hybrid layer with the adsorption of DNA nucleic acid bases.

Substituent and Solvent Effects on the Electronic and Structural Properties of Silacyclopropylidenoids

The isomeric structures, energies, and properties of the substituted silacyclopropylidenoids, SiC₂H₃RLiBr (R= –H, –CH₃, –SiH₃, –CN, –OH, –NH₂), were studied by <em>ab initio</em> calculations at the MP2/6-311+G(d,p) level of theory. The calculations indicate that each of SiC₂H₃RLiBrs for R= –H, –CH₃, –SiH₃, –CN, –OH, –NH₂has three stationary structures: silacyclopropylidenoid (<strong>S</strong>), tetrahedral (<strong>T1</strong> or <strong>T2</strong>), and inverted (<strong>I</strong>). The conductor–like polarizable continuum model (CPCM) using various solvents (dimethyl sulfoxide (ε = 46.7), acetone (ε = 21.0), tetrahydrofuran (ε = 7.5), and diethyl ether (ε = 4.3)) has been applied to compute single point energies for title molecules. In addition, the molecular electrostatic potential maps, natural bond orbitals, and the frontier molecular orbitals of substituted silacyclopropylidenoids were calculated.

Nontemplate synthesis, characterization and theoretical study of tetraazamacrocycles

The syntheses of new tetraaza macrocyclic compounds of variable ring sizes by non-template methods and their characterization with the help of elemental analysis and spectroscopic techniques (FT-IR, 1H-NMR, and 13C-NMR) have been reported in detail. The vibrational frequencies determined experimentally are compared with those obtained theoretically from density functional theory (DFT) and Hartree-Fock (HF) calculations. The comparisons between the experimental and theoretical results indicate that B3LYP level with both the 3-21G(d) and 6-31G+(d,p) basis sets is able to provide satisfactory results for predicting IR properties. The frontier molecular orbital diagrams and molecular electrostatic potential maps of title compounds have been also calculated and visualized at the B3LYP/6-31G+(d,p) level of theory.

Spectroscopic and theoretical insights on determination of binding strength and molecular structure for the supramolecular complexes of a designed bisporphyrin with C60 and C70

The present article examines the binding affinity of the newly designed Zn2-bisporphyrin molecule, syn-1, towards C60 and C70 in toluene medium. The investigation is carried out by UV-vis spectrophotometric, steady state and time-resolved fluorescence spectroscopic techniques. The bisporphyrin, syn-1, serves as an effective and selective molecular tweezer for C70 as average value of binding constants (K) for the non-covalent complexes of syn-1 with C60 and C70 are estimated to be 1.65 × 104 and 1.05 × 105 dm3 · mol-1, respectively. Binding of C70 in the cleft of syn-1 is clearly demonstrated by the quantum chemical calculations at ab initio level of theory. Molecular electrostatic potential maps demonstrate significant redistribution of charges in these supramolecules. Proton NMR studies suggest that the C70 moiety remains at the shallow part of the cleft of syn-1.