Computer-aided molecular design and optimization of potent inhibitors disrupting APC‒Asef interaction.

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. At initial diagnosis, approximately 20% of patients are diagnosed with metastatic CRC (mCRC). Although the APC‒Asef interaction is a well-established target for mCRC therapy, the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging endeavor. In this study, we identified a novel structural scaffold based on MAI inhibitors, the first-in-class APC‒Asef inhibitors we reported previously. ONIOM model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed, and 24-fold greater potency was obtained with the best inhibitor compared to the parental compound. In addition, the cocrystal structure validated that the two-layer π‒π stacking interactions were essential for inhibitor stabilization in the bound state. Furthermore, in vitro and in vivo studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC‒Asef interaction. These results provide an intrinsic structural basis to further explore drug-like molecules for APC‒Asef-mediated CRC therapy.

Binding interactions and in silico ADME prediction of isoconessimine derivatives as potent acetylcholinesterase inhibitors.

In pursuit of new acetylcholinesterase (AChE) inhibitors for treating Alzheimer's disease (AD), a series of ten previously synthesized isoconessimine compounds (7a-7j) was in silico investigated for their binding interactions with AChE and pharmacokinetics based on absorption, distribution, metabolism, and excretion (ADME) properties using molecular docking, ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) method and SwissADME tools. Docking experiments showed that all compounds bind within the active site gorge of AChE (PDB entry 1C2B), posing its aryloxy-substitutional ethyl group to catalytic site and conessine skeleton to peripheral anionic site. ONIOM interaction energy was used as an ONIOM score to improve docking score, and it ranked 7b as the most potent AChE inhibitor, in agreement with previous experiment. Residues, ASP74, TRP86, GLY122, GLU202, TRP286, GLU292, SER293, ILE294, TYR337, TYR341, and HIS447 were identified as important for the binding of the AChE-isoconessimine complex. The SwissADME investigation suggested that four compounds (7a, 7c, 7d and 7f) agree with the rules of drug-likeness. The steric and electronic effects on the aryloxy-substitutional ethyl group as important factors in the AChE inhibition were also discussed, which brings a better understanding of Alzheimer's disease drug development.

A quantum mechanical approach to the oxidation mechanism of graphene oxide (GO).

Elucidation of the reaction mechanism concerning the oxidation above the face and at the edge of a large, oxidized graphene (GO) cluster, namely C80H22O, by molecular oxygen in the first excited state (1Δg) was achieved with quantum mechanical calculations using the ONIOM two-layer method. Oxidation on the face of the aforementioned cluster leads to the formation of an ozone molecule, whereas oxygen molecule attack at the edge of the oxidized graphene surface either launches an ozonide -a five-membered ring species- formation during its outward approach or an 1,3-dioxetane -a four-membered ring species- production along its inward invasion. A detailed examination of the proposed pathways suggests that the ozonide formation should overcome almost one and a half times an adiabatic energy barrier with respect to the ozone production and is strongly exergonic by up to -50.1 kcal mol-1, supporting the experimental findings that both compounds are critically involved in the explosive deoxygenation of GO. On the other hand, the 1,3-dioxetane alternative pathway is considered even more exergonic, although it requires an overwhelming adiabatic energy barrier of 29.8 kcal mol-1 to accomplish its target.

Computational modelling and optimization studies of electropentamer for molecular imprinting of DJ-1.

Parkinson's disease (PD) is the most prevalent type of incurable movement disorder. Recent research findings propose that the familial PD-associated molecule DJ-1 exists in cerebrospinal fluid (CSF) and that its levels may be altered as Parkinson's disease advances. By using a molecularly imprinted polymer (MIP) as an artificial receptor, it becomes possible to create a functional MIP with predetermined selectivity for various templates, particularly for the DJ-1 biomarker associated with Parkinson's disease. It mostly depends on molecular recognition via interactions between functional monomers and template molecules. So, the computational methods for the appropriate choice of functional monomers for creating molecular imprinting electropolymers (MIEPs) with particular recognition for the detection of DJ-1, a pivotal biomarker involved in PD, are undertaken in this study. Here, molecular docking, molecular dynamics simulations (MD), molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methods, and quantum mechanical calculation have been applied to investigate the intermolecular interaction between DJ-1 and several functional electropentamers, viz., polypyrrole (PPy), poly(3,4-ethylenedioxythiophene) (PEDOT), poly(o-aminophenol) (POAP), and polythiophene (PTS). In this context, the electropentamers were selected to mimic the imprinted electropolymer system. We analyzed the most stable configurations of the formed complexes involving DJ-1 and electropentamers as a model system for MIEPs. Among these, PEDOT exhibited a more uniform arrangement around DJ-1, engaging in numerous van der Waals, H-bond, electrostatic, and hydrophobic interactions. Hence, it can be regarded as a preferable choice for synthesizing a MIP for DJ-1 recognition. Thus, it will aid in selecting a suitable functional monomer, which is of greater significance in the design and development of selective DJ-1/MIP sensors.

Inhibitory potential of furanocoumarins against cyclin dependent kinase 4 using integrated docking, molecular dynamics and ONIOM methods.

Cyclin Dependent Kinase 4 (CDK4) is vital in the process of cell-cycle and serves as a G1 phase checkpoint in cell division. Selective antagonists of CDK4 which are in use as clinical chemotherapeutics cause various side-effects in patients. Furanocoumarins induce anti-cancerous effects in a range of human tumours. Therefore, targeting these compounds against CDK4 is anticipated to enhance therapeutic effectiveness. This work intended to explore the CDK4 inhibitory potential of 50 furanocoumarin molecules, using a comprehensive approach that integrates the processes of docking, drug-likeness, pharmacokinetic analysis, molecular dynamics simulations and ONIOM (Our own N-layered Integrated molecular Orbital and Molecular mechanics) methods. The top five best docked compounds obtained from docking studies were screened for subsequent analysis. The molecules displayed good pharmacokinetic properties and no toxicity. Epoxybergamottin, dihydroxybergamottin and notopterol were found to inhabit the ATP-binding zone of CDK4 with substantial stability and negative binding free energy forming hydrogen bonds with key catalytic residues of the protein. Notopterol exhibiting the highest binding energy was subjected to ONIOM calculations wherein the hydrogen bonding interactions were retained with significant negative interaction energy. Hence, through these series of computerised methods, notopterol was screened as a potent CDK4 inhibitor and can act as a starting point in successive processes of drug design.Communicated by Ramaswamy H. Sarma.

Structural basis for inhibition of a GH116 ß-glucosidase and its missense mutants by GBA2 inhibitors: Crystallographic and quantum chemical study.

The crystal structure of the Thermoanaerobacterium xylanolyticum in glycoside hydrolase family 116 (TxGH116) ß-glucosidase provides a structural model for human GBA2 glucosylceramidase, an enzyme defective in hereditary spastic paraplegia and a potential therapeutic target for treating Gaucher disease. To assess the therapeutic potential of known inhibitors, the X-ray structure of TxGH116 in complex with isofagomine (IFG) was determined at 2.0 Å resolution and showed the IFG bound in a relaxed chair conformation. The binding of IFG and 7 other iminosugar inhibitors to wild-type and mutant enzymes (Asp508His and Arg786His) mimicking GBA2 pathogenic variants was then evaluated computationally by two-layered ONIOM calculations (at the B3LYP:PM7 level). Calculations showed that six charged residues, Glu441, Asp452, His507, Asp593, Glu777, and Arg786 influence inhibitor binding most. His507, Glu777 and Arg786, form strong hydrogen bonds with the inhibitors (∼1.4-1.6 Å). Thus, the missense mutation of one of these residues in Arg786His has a greater effect on the interaction energies for all inhibitors compared to Asp508His. In line with the experimental data for the inhibitors that have been tested, the favorable interaction energy between the inhibitors and the TxGH116 protein followed the trend: isofagomine > 1-deoxynojirimycin > glucoimidazole > N-butyl-deoxynojirimycin ≈ N-nonyl-deoxynojirimycin > conduritol B epoxide ≈ azepane 1 > azepane 2. The obtained structural and energetic properties and comparison to the GBA2 model can lead to understanding of structural requirement for inhibitor binding in GH116 to aid the design of high potency GBA2 inhibitors.

Dispersion-corrected DFT calculations and umbrella sampling simulations to investigate stability of Chrysin-cyclodextrin inclusion complexes.

The study of inclusion complexes of Chrysin (ChR) with three forms of cyclodextrins (CDs) α-, ß-, and γ-CD was accomplished to examine the stability of ChR inside the central cavities of CDs. The aim of study was to identify the most suitable form of CD to improve the hydro-solubility of poorly soluble ChR bioactive molecule. Microsecond timescale molecular dynamics (MD) simulations were performed on four inclusion complexes (α-CD/ChR, ß-CD/ChR, and two conformations of γ-CD/ChR) to examine the dynamics of ChR inside the cavity of CDs. The first conformation of γ-CD/ChR inclusion complex (γ-CD1/ChR) was identified to possess the highest affinity between host and guest molecule on the basis of binding energy calculated by employing Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and umbrella sampling simulations. To further strengthen the claims of classical and biased MD studies, Our own N-layered Integrated molecular Orbital and Molecular mechanics (ONIOM) (wB97XD/6-311+g(d,p):pm7) calculations were performed on the selected inclusion complexes. The ONIOM based complexation energy reaffirmed that ChR had highest affinity for the γ-CD1 host molecule. Further, the non-covalent interaction analysis was conducted using Multiwfn software on QM-optimized inclusion complexes with wB97XD/6-311+G(d,p) model chemistry, revealing non-covalent interactions between ChR and CDs. This atomic level information helped us to gain better insights into critical atoms of ChR and CD that participated in intermolecular interactions and identify γ-CD as a suitable host molecule for improving the hydro-solubulity of ChR. The structural insights would help to derive new derivatives of γ-CD with better host capacity.

Calculating 13 C NMR chemical shifts of large molecules using the eXtended ONIOM method at high accuracy with a low cost.

Fragmentation-based methods for nuclear magnetic resonance (NMR) chemical shift calculations have become more and more popular in first-principles calculations of large molecules. However, there are many options for a fragmentation-based method to select, such as theoretical methods, fragmentation schemes, the number of levels of theory, etc. It is important to study the optimal combination of the options to achieve a good balance between accuracy and efficiency. Here we investigate different combinations of options used by a fragmentation-based method, the eXtended ONIOM (XO) method, for 13 C chemical shift calculations on a set of organic and biological molecules. We found that: (1) introducing Hartree-Fock exchange into density functional theory (DFT) could reduce the calculation error due to fragmentation in contrast to pure DFT functionals, while a hybrid functional, xOPBE, is generally recommended; (2) fragmentation schemes generated from the molecular tailoring approach (MTA) with small level parameter n, for example, n = 2 and the degree-based fragmentation method (DBFM) with n = 1, are sufficient to achieve satisfactory accuracy; (3) the two-level XO (XO2) NMR calculation is superior to the calculation with only one level of theory, as the second level (i.e., low level) of theory provides a way to well describe the long-range effect. These findings are beneficial to practical applications of fragmentation-based methods for NMR chemical shift calculations of large molecules.

Computational Insights on the Hydride and Proton Transfer Mechanisms of D-Arginine Dehydrogenase.

D-Arginine dehydrogenase from Pseudomonas aeruginosa (PaDADH) is an amine oxidase which catalyzes the conversion of D-arginine into iminoarginine. It contains a non-covalent FAD cofactor that is involved in the oxidation mechanism. Based on substrate, solvent, and multiple kinetic isotope effects studies, a stepwise hydride transfer mechanism is proposed. It was shown that D-arginine binds to the active site of enzyme as α-amino group protonated, and it is deprotonated before a hydride ion is transferred from its α-C to FAD. Based on a mutagenesis study, it was concluded that a water molecule is the most likely catalytic base responsible from the deprotonation of α-amino group. In this study, we formulated computational models based on ONIOM method to elucidate the oxidation mechanism of D-arginine into iminoarginine using the crystal structure of enzyme complexed with iminoarginine. The calculations showed that Arg222, Arg305, Tyr249, Glu87, His 48, and two active site water molecules play key roles in binding and catalysis. Model systems showed that the deprotonation step occurs prior to hydride transfer step, and active site water molecule(s) may have participated in the deprotonation process.

A mechanistic insight for the biosynthesis of N,N-dimethyltryptamine: An ONIOM theoretical approach.

Psychoactive natural products are potent serotonergic agonists capable of modulating brain functions such as memory and cognition. These substances have shown therapeutic potential for treating various mental disorders. The fact that N,N-dimethyltryptamine (DMT) is produced endogenously in several plants and animals, including humans, makes it particularly attractive. As an amino acid-derived alkaloid, the DMT biosynthetic pathway is part of the L-tryptophan biochemical cascade and can be divided into the decarboxylation by an aromatic L-amino acid decarboxylase (AADC) for tryptamine formation and the subsequent double-methylation by the indolethylamine-N-methyltransferase (INMT) through the cofactor S-adenosyl-L-methionine (SAM), a methyl donor. Unlike the decarboxylation mechanism of L-tryptophan, the molecular details of the double methylation of tryptamine have not been elucidated. Therefore, we propose an in silico model using molecular dynamics (MD), non-covalent interaction index (NCI) and density functional theory (DFT) calculations with the ONIOM QM:MM B3LYP/6-31+G(d,p):MM/UFF level of theory. Based on the obtained energetic data, the potential energy surface (PES) indicates an SN2 mechanism profile, with the second methylation energy barrier being the rate-limiting step with δG‡=60kJ∙mol-1 larger than the previous methylation, following the NCI analysis showing more repulsive interactions for the second transition state. In addition, the hybridization information of each reaction step provides geometric details about the double-methylation.

Computational and experimental examinations of new antitumor palladium(II) complex: CT-DNA-/BSA-binding, in-silico prediction, DFT perspective, docking, molecular dynamics simulation and ONIOM.

Since the design of metal complexes with better biological activities is important, herein a new palladium(II) complex bearing en and acac (en and acac stand for ethylenediamine and acetylacetonato, respectively) as its ligands, [Pd(en)(acac)]NO3 complex, was synthesized and fully characterized. Quantum chemical computations of the palladium(II) complex were done via DFT/B3LYP method. Cytotoxicity activity of the new compound on leukemia cell line (K562) was assessed via MTT method. The findings indicated that the metal complex has remarkable cytotoxic effect than cisplatin. OSIRIS DataWarrior software was employed to calculate in-silico physicochemical and toxicity parameters of the synthesized complex which rendered significant results. To comprehend the interaction type of new metal compound with macromolecules, the in depth investigation of interaction of mentioned complex with CT-DNA and BSA was accomplished by fluorescence, UV-Visible absorption spectroscopy, viscosity measurement, gel electrophoresis, FRET analysis and circular dichroism (CD) spectroscopy. On the other hand, computational molecular docking was carried out and the obtained data demonstrated that H-bond and van der Waals forces are the dominant forces for the binding of the compound to the mentioned biomolecules. Molecular dynamics simulation was also done and confirmed the stability of best docked pose of palladium(II) complex inside DNA or BSA over the time and in presence of water solvent. Also, Our own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM) methodology based on the hybridization of quantum mechanics and molecular mechanics (QM/MM) methodology was accomplished to inquire about binding of Pd(II) complex with DNA or BSA.Communicated by Ramaswamy H. Sarma.

New biologically active Pd(II) complex was synthesized and characterized.The in silico studies of the designed complex and its ligands were accomplished by OSIRIS DataWarrior softwareInteraction with CT-DNA and BSA was assessed by various spectroscopic methods.Molecular docking simulation supported the interaction with both macromolecules.Based on ONIOM analysis, the structures of the complex and biomolecules are altered after binding.

Quantum-based modeling implies that bidentate Arg89-substrate binding enhances serine/threonine protein phosphatase-2A(PPP2R5D/PPP2R1A/PPP2CA)-mediated dephosphorylation.

PP2A-serine/threonine protein phosphatases function as heterotrimeric holoenzymes, composed of a common scaffold (A-subunit encoded by PPP2R1A/PPP2R1B), a common catalytic (C-subunit encoded by PPP2CA/PPP2CB), and one of many variable regulatory (B) subunits. The site of phosphoprotein phosphatase (PPP) hydrolysis features a bimetal system (M1/M2), an associated bridge hydroxide [W1(OH-)], and a highly-conserved core sequence. In the presumptive common mechanism, the phosphoprotein's seryl/threonyl phosphate coordinates the M1/M2 system, W1(OH-) attacks the central P atom, rupturing the antipodal bond, and simultaneously, a histidine/aspartate tandem protonates the exiting seryl/threonyl alkoxide. Based on studies of PPP5C, a conserved arginine proximal to M1 is also expected to bind the substrate's phosphate group in a bidentate fashion. However, in PP2A isozymes, the role of the arginine (Arg89) in hydrolysis is not clear because two independent structures for PP2A(PPP2R5C) and PP2A(PPP2R5D) show that Arg89 engages in a weak salt bridge at the B:C interface. These observations raise the question of whether hydrolysis proceeds with or without direct involvement of Arg89. The interaction of Arg89 with B:Glu198 in PP2A(PPP2R5D) is significant because the pathogenic E198K variant of B56δ is associated with irregular protein phosphorylation levels and consequent developmental disorders (Jordan's Syndrome; OMIM #616355). In this study, we perform quantum-based hybrid [ONIOM(UB3LYP/6-31G(d):UPM7)] calculations on 39-residue models of the PP2A(PPP2R5D)/pSer (phosphoserine) system to estimate activation barriers for hydrolysis in the presence of bidentate Arg89-substrate binding and when Arg89 is otherwise engaged in the salt-bridge interaction. Our solvation-corrected results yield ΔH‡ ≈ ΔE‡ = +15.5 kcal/mol for the former case, versus +18.8 kcal/mol for the latter, indicating that bidentate Arg89-substrate binding is critical for optimal catalytic function of the enzyme. We speculate that PP2A(PPP2R5D) activity is suppressed by B:Glu198 sequestration of C:Arg89 under native conditions, whereas the PP2A(PPP2R5D)-holoenzyme containing the E198K variant has a positively-charged lysine in this position that alters normal function.

Theoretical investigations of free energy of binding and chiral recognition studies of (R)- and (S)-Noradrenaline towards ß-cyclodextrin.

Noradrenaline (NA), one of the important excitatory catecholamine neurotransmitters, is used as a medication for Parkinson's Disease (PD). The ß-cyclodextrin (ß-CD) is one of the most effective drug carrier & also used in chiral separation. So, in this theoretical investigation, the R/S-Noradrenaline (R/S-NA) forms binding & chiral recognition mechanisms and energies with ß-CD were explored. Using the AutoDock, R/S forms were first docked into the cavity of ß-CD giving host-guest complexes with the free energy of binding for S-NA (-4.81 kcal/mol) larger than R-NA (-4.53 kcal/mol). The host-guest inclusion 1:1 complexes between R/S-NA and ß-CD have been also modeled and optimized with ONIOM2 (B3LYP/6-31g++DP: PM6) method by using the Gaussian software. Further, frequency calculations were carried out to obtain the free energies. In comparison to the R-NA (-54.59 kcal/mol), it was observed that the S-NA (-56.48 kcal/mol) with ß-CD is more stable. Furthermore, the H-bond results from molecular dynamics simulation revealed that S-NA/ß-CD was more stable than R-NA/ß-CD. In addition, the thermodynamic properties, vibrational analysis (IR), HOMO-LUMO band gap energy, inter molecular hydrogen bond interactions, and conformational analysis were investigated for both the R/S forms to support & compare the stability of the inclusion complex. These inclusion & high stability of S-NA/ß-CD and in turn its theoretical chiral recognition behavior observed agreeing well with the reported NMR experimental data have implications in drug delivery and chiral separation research.

Transition metal (X = Mn, Fe, Co, Ni, Cu, Zn)-doped graphene as gas sensor for CO2 and NO2 detection: a molecular modeling framework by DFT perspective.

CONTEXT: In this research, CO2 and NO2 adsorption on doped nanographene (NG) sheets with transition metals (Fe, Ni, Zn) and (Mn, Co, Cu), respectively, have been applied for scavenging of these toxic gases as the environmental pollutants. The values of changes of atomic charge density have illustrated a more significant charge transfer for Ni-doped C-NG through CO2 adsorption and a more remarkable charge transfer for Co-doped C-NG through NO2 adsorption. The data of NMR spectroscopy has depicted several fluctuations around the graph of Zn-doped on the nanographene surface. The thermodynamic results from IR spectroscopy have indicated that [Formula: see text] values are almost similar for doped metal transitions of Mn, Co, and Cu on the C-NG nanosheet, while [Formula: see text] has the largest gap of Gibbs free energy adsorption with dipole moment. METHODS: The Langmuir adsorption model with a three-layered ONIOM using CAM-B3LYP functional accompanying LANL2DZ, EPR-III and 6-31 + G (d,p) basis sets due to Gaussian 16 revision C.01 program on the complexes of CO2 → (Fe, Ni, Zn) and NO2 → (Mn, Co, Cu) doped on the C-NG has been accomplished. Then, NMR and IR spectroscopy, nuclear quadrupole resonance, and natural bond orbital analysis have been accomplished for evaluating chemical shielding tensors, thermodynamic properties, electric potential, and occupancy fluctuation through bond orbitals, respectively. In addition, frontier orbitals of LUMO, HOMO, and also a series of chemical reactivity parameters have been calculated. Finally, time-dependent-DFT method due to UV-VIS spectrums has been accomplished to discern the low-lying excited states of CO2 and NO2 adsorption on the (Fe, Ni, Zn) and (Mn, Co, Cu), respectively, doped C-NG sheet.

DFT and ONIOM Simulation of 1,3-Butadiene Polymerization Catalyzed by Neodymium-Based Ziegler-Natta System.

Using modern methods of quantum chemistry, a theoretical substantiation of the high cis-stereospecificity of 1,3-butadiene polymerization catalyzed by the neodymium-based Ziegler-Natta system was carried out. For DFT and ONIOM simulation, the most cis-stereospecific active site of the catalytic system was used. By analyzing the total energy, as well as the enthalpy and Gibbs free energy of the simulated catalytically active centers, it was found that the coordination of 1,3-butadiene in the trans-form was more favorable than in the cis-form by 11 kJ/mol. However, as a result of π-allylic insertion mechanism modeling, it was found that the activation energy of cis-1,3-butadiene insertion into the π-allylic neodymium-carbon bond of the terminal group on the reactive growing chain was 10-15 kJ/mol lower than the activation energy of trans-1,3-butadiene insertion. The activation energies did not change when both trans-1,4-butadiene and cis-1,4-butadiene were used for modeling. That is, 1,4-cis-regulation was due not to the primary coordination of 1,3-butadiene in its cis-configuration, but to its lower energy of attachment to the active site. The obtained results allowed us to clarify the mechanism of the high cis-stereospecificity of 1,3-butadiene polymerization by the neodymium-based Ziegler-Natta system.

Binding profile of a mixed-ligand silver(I) complex with DNA and Topoisomerase I.

A new mixed-ligand Ag(I) complex, [Ag(daf)(phen)]NO3 (daf = 4,5-diazafluoren-9-one and dian = N-(4,5-diazafluoren-9-ylidene)aniline), was synthesized. The elemental analysis, FTIR, 1HNMR, UV-Vis spectroscopy, cyclic voltammetry, and DFT (Density Functional Theory) geometry optimization method were applied in order to predict the Ag(I) complex structure which concluded to a distorted tetrahedral N4 coordination around the Ag(I) center. A detailed in silico analysis of the bioaffinity of the complex to DNA and human DNA-Topoisomerase I was conducted using molecular docking simulations and ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) techniques. In this overall scenario, the results suggest the dominance of π-π stacking interactions of the heteroaromatic ligands in the intercalating pocket of DNA and the active site of the enzyme and the rational correlation between being a good intercalator and a potent Topoisomerase I inhibitor. In vitro DNA-binding experiments by spectrophotometric, spectrofluorometric, Voltammetric, and viscometric techniques at physiological pH also confirmed the computational results. The complex inhibited MCF-7 cell growth in a dose-dependent manner while being nontoxic on HUVEC normal cells.

Quantum chemical studies on the binding domain of SARS-CoV-2 S-protein: human ACE2 interface complex.

A two-layer ONIOM(B3LYP/6-31G*:PM7) method is used to model the binding of several drug/drug-like molecules (L) at the SARS-CoV-2 S-protein: human ACE2 protein interface cavity. The selected molecules include a set of thirty-five ligands from the study of Smith and Smith which showed a high docking score in the range of -7.0 to -7.7 kcal/mol and another set of seven repurposing drugs, viz. favipiravir, remdesivir, EIDD, galidesivir, triazavirin, ruxolitinib, and baricitinib. The ONIOM model of the cavity (M) showed a highly polarized electron distribution along its top-to-bottom direction while Ls with lengths in the range 1.0 - 1.5 nm fitted well inside the cavity in a head-to-tail fashion to yield ML complexes. The ligands showed a large variation in the ONIOM-level binding energy (Eb), in the range -2.7 to -85.4 kcal/mol. The Eb of ML complexes better than -40.0 kcal/mol is observed for myricetin, fidarestat, protirelin, m-digallic acid, glucogallin, benserazide hydrochlorideseradie, remdesivir, tazobactum, sapropterin, nitrofurantoin, quinonoid, pyruvic acid calcium isoniazid, and aspartame, and among them the highest Eb -85.4 kcal/mol is observed for myricetin. A hydroxy substitution is suggested for the phenyl ring of aspartame to improve its binding behavior at the cavity, and the resulting ligand 43 showed the best Eb -84.5 kcal/mol. The ONIOM-level study is found to be effective for the interpretation of the noncovalent interactions resulting from residues such as arginine, histidine, tyrosine, lysine, carboxylate, and amide moieties in the active site and suggests rational design strategies for COVID-19 drug development.Communicated by Ramaswamy H. Sarma.

Virtual Screening and Quantum Chemistry Analysis for SARS-CoV-2 RNA-Dependent RNA Polymerase Using the ChEMBL Database: Reproduction of the Remdesivir-RTP and Favipiravir-RTP Binding Modes Obtained from Cryo-EM Experiments with High Binding Affinity.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogenic cause of coronavirus disease 2019 (COVID-19). The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a potential target for the treatment of COVID-19. An RdRp complex:dsRNA structure suitable for docking simulations was prepared using a cryo-electron microscopy (cryo-EM) structure (PDB ID: 7AAP; resolution, 2.60 Å) that was reported recently. Structural refinement was performed using energy calculations. Structure-based virtual screening was performed using the ChEMBL database. Through 1,838,257 screenings, 249 drugs (37 approved, 93 clinical, and 119 preclinical drugs) were predicted to exhibit a high binding affinity for the RdRp complex:dsRNA. Nine nucleoside triphosphate analogs with anti-viral activity were included among these hit drugs, and among them, remdesivir-ribonucleoside triphosphate and favipiravir-ribonucleoside triphosphate adopted a similar docking mode as that observed in the cryo-EM structure. Additional docking simulations for the predicted compounds with high binding affinity for the RdRp complex:dsRNA suggested that 184 bioactive compounds could be anti-SARS-CoV-2 drug candidates. The hit bioactive compounds mainly consisted of a typical noncovalent major groove binder for dsRNA. Three-layer ONIOM (MP2/6-31G:AM1:AMBER) geometry optimization calculations and frequency analyses (MP2/6-31G:AMBER) were performed to estimate the binding free energy of a representative bioactive compound obtained from the docking simulation, and the fragment molecular orbital calculation at the MP2/6-31G level of theory was subsequently performed for analyzing the detailed interactions. The procedure used in this study represents a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that could significantly shorten the clinical development period for drug repositioning.

A multiscale ONIOM study of the buckminsterfullerene (C60) Diels-Alder reaction: from model design to reaction path analysis.

The hybrid ONIOM (Our own N-layered Integrated molecular Orbital and molecular Mechanics) formalism is employed to investigate the Diels-Alder reaction of the buckminsterfullerene C60. Our computations suggest that the ONIOM2(M06-2X/6-31G(d): SVWN/STO-3G) model, enclosing both the diene and the pyracyclene fragment of C60 in the higher-layer, provides a reasonable trade-off between accuracy and computational cost as it comes to predicting reaction energetics. Moreover, the frontier molecular orbital (FMO) theory and activation strain model (ASM) are jointly relied on to rationalize the effect of -OH and -CN substituents on the activation barrier of this reaction. Finally, reaction paths are scrutinized to get insight into the various forces underpinning the process of cycloadduct formation.

Analysis of Fluctuation in the Heme-Binding Pocket and Heme Distortion in Hemoglobin and Myoglobin.

Heme is located in the active site of proteins and has diverse and important biological functions, such as electron transfer and oxygen transport and/or storage. The distortion of heme porphyrin is considered an important factor for the diverse functions of heme because it correlates with the physical properties of heme, such as oxygen affinity and redox potential. Therefore, clarification of the relationship between heme distortion and the protein environment is crucial in protein science. Here, we analyzed the fluctuation in heme distortion in the protein environment for hemoglobin and myoglobin using molecular dynamics (MD) simulations and quantum mechanical (QM) calculations as well as statistical analysis of the protein structures of hemoglobin and myoglobin stored in Protein Data Bank. Our computation and statistical analysis showed that the protein environment for hemoglobin and myoglobin prominently affects the doming distortion of heme porphyrin, which correlates with its oxygen affinity, and that the magnitude of distortion is different between hemoglobin and myoglobin. These results suggest that heme distortion is affected by its protein environment and fluctuates around its fitted conformation, leading to physical properties that are appropriate for protein functions.