3D-QSAR and molecular docking studies of peptide-hybrids as dengue virus NS2B/NS3 protease inhibitors.

Global warming and climate change have made dengue disease a global health issue. More than 50 % of the world's population is at danger of dengue virus (DENV) infection, according to the World Health Organization (WHO). Therefore, a clinically approved dengue fever vaccination and effective treatment are needed. Peptide medication development is new pharmaceutical research. Here we intend to recognize the structural features inhibiting the DENV NS2B/NS3 serine protease for a series of peptide-hybrid inhibitors (R1-R2-Lys-R3-NH2) by the 3D-QSAR technique. Comparative molecular field analysis (q2 = 0.613, r2 = 0.938, r2pred = 0.820) and comparative molecular similarity indices analysis (q2 = 0.640, r2 = 0.928, r2pred = 0.693) were established, revealing minor, electropositive, H-bond acceptor groups at the R1 position, minor, electropositive, H-bond donor groups at the R2 position, and bulky, hydrophobic groups at the R3 position for higher inhibitory activity. Docking studies revealed extensive H-bond and hydrophobic interactions in the binding of tripeptide analogues to the NS2B/NS3 protease. This study provides an insight into the key structural features for the design of peptide-based inhibitors of DENV NS2B/NS3 protease.

Mechanism of cationic ring-opening polymerisation of ε-caprolactone using metallocene/borate catalytic systems: a DFT and NCI study on chain initiation, propagation and termination.

We present a comprehensive DFT investigation on the cationic ring-opening polymerisation (CROP) of ε-caprolactone (CL) using zirconocene/borate catalyst systems. All possible pathways of the interaction between cationic species [Cp2ZrMe+] and counteranions, [A-] = [MeB(C6F5)3]- and [B(C6F5)4]-, were examined during chain initiation, propagation, and termination steps. The calculations reveal an active chain-end mechanism with O-alkyl bond cleavage of the polymerisation. The catalytic performance of the two counteranions is found to be identical, and they influence the initial process through stabilisation of the cationic species via non-covalent interactions (NCI), with the [MeB(C6F5)3]- anion stabilising the catalyst-monomer complex more effectively than the [B(C6F5)4]- anion by 24.3 kJ mol-1. The first two propagations are likely the rate-determining step, with calculated free-energy barriers of 61.4-71.2 and 73.9-80.6 kJ mol-1 with and without the anions (A-), respectively. The presence of the counteranion significantly affects the third propagation rate, lowering the barriers up to 20 kJ mol-1. Comparison of the first termination and the third propagation shows that they are not competitive, with the termination being less facile. We also studied the initiation and propagation steps for the hafnocene catalyst and found that the Hf catalyst slightly favours the CL CROP in comparison to the Zr catalyst. Analysis of solvent and dispersion interaction demonstrates that both factors play an important role in the process. NCI analysis reveals weak (van der Waals) interactions at the contacts between the cationic species and the counteranions during the reaction course. Overall, our results offer insights into the structures and interactions involved in the polymerisation.

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.

Computational evaluation of zirconocene catalysts for ε-caprolactone cationic ring-opening polymerization.

This quantum chemical study presents the ligand effect and a structure-property relationship in the cationic ring-opening polymerization (CROP) of ε-caprolactone using zirconocene catalysts. We first examined the effects of catalyst structure on the initiation and chain propagation steps of the CROP process. A total of 54 catalyst structures were investigated to understand the influence of the ligand structure on the stability of the catalyst-monomer complex and polymerization activity. The properties of the catalysts were analyzed in terms of ancillary ligands, ligand substituents, and bridging units. Calculations showed that the polymerization follows a proposed cationic mechanism, with ring opening occurring via alkyl-bond cleavage. A correlation between complex stability and activation energy was also observed, with ligand substituents dominating in both steps. While the ancillary ligands directly affect the HOMO energy level, the bridges are mainly responsible for the catalyst geometries, resulting in reduced complex stability and higher activation energy for the propagation step. This study contributes to a better understanding of the structural characteristics of zirconocene catalysts, which offers guidance for improving CROP activities in lactone polymerization.

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.

Multiscale QM/MM Simulations Identify the Roles of Asp239 and 1-OH···Nucleophile in Transition State Stabilization in Arabidopsis thaliana Cell-Wall Invertase 1.

Arabidopsis thaliana cell-wall invertase 1 (AtCWIN1), a key enzyme in sucrose metabolism in plants, catalyzes the hydrolysis of sucrose into fructose and glucose. AtCWIN1 belongs to the glycoside hydrolase GH-J clan, where two carboxylate residues (Asp23 and Glu203 in AtCWIN1) are well documented as a nucleophile and an acid/base catalyst. However, details at the atomic level about the role of neighboring residues and enzyme-substrate interactions during catalysis are not fully understood. Here, quantum mechanical/molecular mechanical (QM/MM) free-energy simulations were carried out to clarify the origin of the observed decreased rates in Asp239Ala, Asp239Asn, and Asp239Phe in AtCWIN1 compared to the wild type and delineate the role of Asp239 in catalysis. The glycosylation and deglycosylation steps were considered in both wild type and mutants. Deglycosylation is predicted to be the rate-determining step in the reaction, with a calculated overall free-energy barrier of 15.9 kcal/mol, consistent with the experimental barrier (15.3 kcal/mol). During the reaction, the -1 furanosyl ring underwent a conformational change corresponding to 3E ↔ [E2]⧧ ↔ 1E according to the nomenclature of saccharide structures along the full catalytic reaction. Asp239 was found to stabilize not only the transition state but also the fructosyl-enzyme intermediate, which explains findings from previous structural and mutagenesis experiments. The 1-OH···nucleophile interaction has been found to provide an important contribution to the transition state stabilization, with a contribution of ∼7 kcal/mol, and affected glycosylation more significantly than deglycosylation. This study provides molecular insights that improve the current understanding of sucrose binding and hydrolysis in members of clan GH-J, which may benefit protein engineering research. Finally, a rationale on the sucrose inhibitor configuration in chicory 1-FEH IIa, proposed a long time ago in the literature, is also provided based on the QM/MM calculations.

A computational study of the reaction mechanism and stereospecificity of dihydropyrimidinase.

Dihydropyrimidinase (DHPase) is a key enzyme in the pyrimidine pathway, the catabolic route for synthesis of ß-amino acids. It catalyses the reversible conversion of 5,6-dihydrouracil (DHU) or 5,6-dihydrothymine (DHT) to the corresponding N-carbamoyl-ß-amino acids. This enzyme has the potential to be used as a tool in the production of ß-amino acids. Here, the reaction mechanism and origin of stereospecificity of DHPases from Saccharomyces kluyveri and Sinorhizobium meliloti CECT4114 were investigated and compared using a quantum mechanical cluster approach based on density functional theory. Two models of the enzyme active site were designed from the X-ray crystal structure of the native enzyme: a small cluster to characterize the mechanism and the stationary points and a large model to probe the stereospecificity and the role of stereo-gate-loop (SGL) residues. It is shown that a hydroxide ion first performs a nucleophilic attack on the substrate, followed by the abstraction of a proton by Asp358, which occurs concertedly with protonation of the ring nitrogen by the same residue. For the DHT substrate, the enzyme displays a preference for the L-configuration, in good agreement with experimental observation. Comparison of the reaction energetics of the two models reveals the importance of SGL residues in the stereospecificity of catalysis. The role of the conserved Tyr172 residue in transition-state stabilization is confirmed as the Tyr172Phe mutation increases the activation barrier of the reaction by ∼8 kcal mol-1. A detailed understanding of the catalytic mechanism of the enzyme could offer insight for engineering in order to enhance its activity and substrate scope.

Role of water coordination at zinc binding site and its catalytic pathway of dizinc creatininase: insights from quantum cluster approach.

Creatininase is a key enzyme of creatinine-metabolizing pathway in mammals, and has a great potential for diagnostic application. It catalyzes the reversible conversion of creatinine to creatine. Here, we investigated its reaction mechanism with density functional theory in conjunction with the quantum cluster approach. Three reaction pathways in which several possible proton transfers assisted by either His178 or a water ligand to Zn1 (Wat2) or both were considered. DFT calculations reveal, depending on Wat2 coordination mode at Zn1, two competitive ring-opening pathways where His178 playing a central role as a proton shuttle or both His178 and Wat2 serving as a dual catalytic role as a base and an acid, respectively. Three elementary steps were proposed for the reaction: the first involves nucleophilic attack by a bridging hydroxide to the substrate and forms a gem-diolate intermediate, followed by a proton transfer from the gem-diolate to His178 (His178 protonation is a required step for efficient proton transfers). Finally, the second proton transfer from the protonated His178 or Wat2 to the amide of substrate leads to the ring opening. The first proton transfer is the rate-limiting step of the whole reaction, in consistent with previous experimental and computational studies. A detailed understanding of the reaction mechanism of the creatininase enzyme family will also be helpful for developing a biosensor for kidney function.

Active site dynamics and catalytic mechanism in arabinan hydrolysis catalyzed by GH43 endo-arabinanase from QM/MM molecular dynamics simulation and potential energy surface.

The endo-1,5-α-L-arabinanases, belonging to glycoside hydrolase family 43 (GH43), catalyse the hydrolysis of α-1,5-arabinofuranosidic bonds in arabinose-containing polysaccharides. These enzymes are proposed targets for industrial and medical applications. Here, molecular dynamics (MD), potential energy surface and free energy (potential of mean force) simulations are undertaken using hybrid quantum mechanical/molecular mechanical (QM/MM) potentials to understand the active site dynamics, catalytic mechanism and the electrostatic influence of active site residues of the GH43 endo-arabinanase from G. stearothermophilus. The calculated results give support to the single-displacement mechanism proposed for the inverting GH43 enzymes: first a proton is transferred from the general acid E201 to the substrate, followed by a nucleophilic attack by water, activated by the general base D27, on the anomer carbon. A conformational change (2E ↔E3 ↔ 4E) in the -1 sugar ring is observed involving a transition state featuring an oxocarbenium ion character. Residues D87, K106, H271 are highlighted as potential targets for future mutation experiments in order to increase the efficiency of the reaction. To our knowledge, this is the first QM/MM study providing molecular insights into the glycosidic bond hydrolysis of a furanoside substrate by an inverting GH in solution.Communicated by Ramaswamy H. Sarma.

Data on electronic structures for the study of ligand effects on the zirconocene-mediated trimethylene carbonate polymerization.

The data presented in this paper are related to the research article entitled "Effect of ligand structure in the trimethylene carbonate polymerization by cationic zirconocene catalysts: A "naked model" DFT study" (Jitonnom and Meelua, 2017) [1]. In this data article, we present 3D molecular information of 29 zirconocene catalysts that differ in electronic and steric properties. The data contains all cationic species along the initiation and first propagation step of the polymerization, which are provided in a PDB format that can be used for further studies.