Synthesis of cinnamate ester–AZT conjugates as potential dual-action HIV-1 integrase and reverse transcriptase inhibitors

Synthetic approaches to a series of novel cinnamate ester–AZT conjugates have been explored and a successful pathway has finally been developed. α-(Halomethyl)cinnamate esters, obtained in high yield by treating benzyl-protected salicylaldehde-derived Baylis–Hillman adducts with acetyl bromide at low temperature, have been treated with propargylamine to afford substrates for click chemistry reactions with azidothymidine (AZT) in the presence of in situ generated Cu(I) catalyst to produce the title compounds.     

Computational models of chemical systems inspired by Braess’ paradox

Systems chemistry is a new discipline which investigates the interactions within a network of chemical reactions. We have studied several computational models of chemical systems inspired by mathematical paradoxes and have found that even simple systems may behave in a counterintuitive, non-linear manner depending upon various conditions. In the present study, we modeled a set of reactions inspired by one such paradox, Braess’ paradox, an interesting phenomenon whereby the introduction of additional capacity (e.g. pathways) in some simple network systems can lead to an unexpected reduction in the overall flow rate of “traffic” through the system. We devised several chemical systems that behaved in this counterintuitive manner; the overall rate of product formation was diminished when an additional pathway was introduced and, conversely, there was an enhancement of product formation when the same interconnecting pathway was removed. We found that, unlike a traffic model, the chemical model needed to include reversible pathways in order to mimic “congestion”—a condition necessary to produce Braess-like behavior. The model was investigated numerically, but a full analytical solution is also included. We propose that this intriguing situation may have interesting implications in chemistry, biochemistry and chemical engineering.     

Study on the drug resistance and the binding mode of HIV-1 integrase with LCA inhibitor

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. The binding mode of the wild type IN core domain and its G140S mutant with L-Chicoric acid (LCA) inhibitor were investigated by using multiple conformation molecular docking and molecular dynamics (MD) simulation. Based on the binding modes, the drug resistance mechanism was explored for the G140S mutant of IN with LCA. The results indicate that the binding site of the G140S mutant of IN core domain with LCA is different from that of the core domain of the wild type IN, which leads to the partial loss of inhibition potency of LCA. The flexibility of the IN functional loop region and the interactions between Mg2 ion and the three key residues (i.e., D64, D116, E152) stimulate the biological operation of IN. The drug resistance also lies in several other important effects, such as the repulsion between LCA and E152 in the G140S mutant core domain, the weakening of K159 binding with LCA and Y143 pointing to the pocket of the G140S mutant. All of the above simulation results agree well with experimental data, which provide us with some helpful information for designing the drug of anti-HIV based on the structure of IN.     

Investigation of formation of dimeric G-quadruplex of HIV-1 integrase inhibitor by nuclear magnetic resonance

In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed by electrospray ionization mass spectrometry （ESI-MS） and circular dichroism （CD）.     

Stability of HIV-1 integrase–ligand complexes: the role of coordinating bonds

It is known that the HIV-1 integrase (IN) strand transfer inhibitors include the chelating fragments forming the coordinating bonds with two Mg²⁺ ions placed in the IN active site. The subject of the article is the role of these coordination bonds on stability of ligand–IN complexes. For this purpose, a set of ligand–IN complexes was investigated theoretically and experimentally. The theoretical model is based on the quantum-chemistry calculations of coordinating bonds geometry and energy. Solvent effects were taking into account using the implicit water model and the two-stage calculation scheme developed previously. For the experimental part of our study a set of the ligands was synthesized, and their IC₅₀ values of IN inhibiting have been measured. It is shown that the main contribution to ligand–IN complexes stability is caused by the substitution of water molecules by the ligand in the first coordination sphere of two Mg²⁺ ions, and the change in the polarization energy of the bulk water. It is shown, that acid–base equilibrium and tautomeric forms of the ligands should be taken into account to improve the prediction ability of the theoretical estimations. All these factors are controlled by the chelating fragments of the ligands. It is demonstrated that our theoretical approach based on the consideration of the coordinating bonds allows to separate active ligands (inhibitors) from inactive ones.     

Synthesis of aromatic-linked polyamine macrocyclic derivatives as HIV-1 entry inhibitors

A series of novel aromatic-linked polyamine macrocyclic derivatives have been synthesized.Their structures were confirmed by MS and ~1H NMR.These compounds exhibited potent anti-HIV-1 activities.     

The first total synthesis of lamellarin α 20-sulfate, a selective inhibitor of HIV-1 integrase

The first total synthesis of lamellarin α 20-sulfate (1), a selective inhibitor of HIV-1 integrase, has been completed. The lamellarin α core in which 13-OH and 20-OH were differentially protected by isopropyl and benzyl groups, respectively, was constructed by using Hinsberg-type pyrrole synthesis and Suzuki-Miyaura coupling as the key reactions. The 20-sulfate was prepared by a sequence including debenzylation of 20-OBn, 2,2,2-trichloroethylsulfation of the resulting 20-OH, deprotection of 13-Oi-Pr, and final reductive cleavage of the 2,2,2-trichloroethyl ester.     

Computational systematic selectivity of the Fasalog inhibitors between ROCK-I and ROCK-II kinase isoforms in Alzheimer’s disease

Human Rho-associated coiled-coil forming kinase (ROCK) is a class of essential neurokinases that consists of two structurally conserved isoforms ROCK-I and ROCK-II; they have been revealed to play distinct roles in the pathogenesis of Alzheimer’s disease (AD) and other neurological disorders. Selective targeting of the two kinase isoforms with small-molecule inhibitors is a great challenge due to the surprisingly high homology in kinase domain (92 %) and the full identity in kinase active site (100 %). Here, we describe a computational protocol to systematically profile the selectivity of Fasudil and its 25 analogs (termed as Fasalogs) between the two kinase isoforms. It is suggested that the substitution of Fasudil’s 1,4-diazepane moiety with rigid ring such as Ripasudil and Dimehtylfasudil would render the resulting inhibitors of ROCK-II over ROCK-I (II-o-I) selectivity, while the substitution with long, flexible group such as H-89 and BDBM92607 tends to have I-o-II selectivity. Structural analysis reveals that the inhibitor affinity is not only determined by the identical active site, but also contributed from the non-identical first and second shells of the site as well as other non-conserved kinase regions, which can indirectly influence the active site and inhibitor binding through allosteric effect. A further kinase assay basically confirms the computational findings, which also exhibits a good consistence with theoretical selectivity over 10 tested samples (R_p = 0.89). In particular, the Fasalog compounds Dimehtylfasudil and H-89 are identified as II-o-I and I-o-II selective inhibitors. They can be considered as promising lead molecular entities to develop new specific ROCK isoform-selective Fasalog inhibitors.     

Computational study on the mechanism of N-phenylimine derivatives’ pyrolysis reaction in the gas phase

In this work, quantum chemistry and kinetics calculations have been performed on the retro-cheletropic ene reactions of N-phenyl-1-methyl-6-methylenecyclohexa-2,4-dienylmethanimine (R1) and N-phenyl-2,2-dimethylbut-3-en (R2). Two major possible mechanisms have been considered and rate constants have been calculated using the transition state theory. The simple Wigner, Eckart zero-curvature tunneling and small-curvature tunneling (SCT) methods were evaluated. The best agreement with experimental rate coefficients was found when SCT correction was applied. A mean deviation of a factor 3 on the rate coefficients is found for the studied reactions at the temperatures of 417 and 773 K. Calculated rate coefficients showed that the tunneling corrections played a critical role in obtaining accurate rate coefficients, especially at lower temperature (417 K). Calculated rate coefficients are in good agreement with the reported experimental data and similar compounds in the case of R1 and R2, respectively. These results support the concerted and stepwise paths for the gas phase reactions of R1 and R2, respectively. Computed kinetic parameters confirmed that R1 had greater reactivity than R2. This trend explains the effects of an extra phenyl-like system on the stability of the transition state and hence increases the R1 rate constant. Calculated rate constants especially at the M06 level are in better agreement with the experimental values than the B3LYP ones. Natural bond orbital (NBO) studies of the reactants and their transition states reveal that their electron delocalization change is an important factor in the determination of the reactivity order for these compounds. Finally, the nature of bond making and breaking during the reactions has been investigated using the concepts of electron charge density and Laplacian in atom in the molecule method.     

Identification of novel PI3Kδ inhibitors by docking,ADMET prediction and molecular dynamics simulations

BackgroundPhosphoinositide-3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ is confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Virtual screening techniques have been used to discover new molecules for developing novel PI3Kδ inhibitors with little side effects.MethodComputer aided drug design method were used to rapidly screen optimal PI3Kδ inhibitors from the Asinex database. Virtual screening based molecular docking was performed to find novel and potential lead compound targeting PI3Kδ, at first. Subsequently, drug likeness studies were carried out on the retrieved hits to evaluate and analyze their drug like properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) for toxicity prediction. Three least toxic compounds were selected for the molecular dynamics (MD) simulations for 30 ns in order to validate its stability inside the active site of PI3Kδ receptor.ResultsBased on the present in silico analysis, two molecules have been identified which occupied the same binding pocket confirming the selection of active site. ASN 16296138 (Glide score: −12.175 kcal/mol, cdocker binding energy: −42.975 kcal/mol and ΔG_bind value: −90.457 kcal/mol) and BAS 00227397 (Glide score: −10.988 kcal/mol, cdocker binding energy: −39.3376 kcal/mol and ΔG_bind value: −81.953 kcal/mol) showed docking affinities comparatively much stronger than those of already reported known inhibitors against PI3Kδ. These two ligand’s behaviors also showed consistency during the simulation of protein-ligand complexes for 30000 ps respectively, which is indicative of its stability in the receptor pocket.ConclusionCompound ASN 16296138 and BAS 00227397 are potential candidates for experimental validation of biological activity against PI3Kδ in future drug discovery studies. This study smoothes the path for the development of novel leads with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of cancer.     

Stability prediction of copper(II) complexes with peptides containing cysteinic disulfide bridge by models based on the connectivity index 3χv

The article is a continuation of our work on the modeling of the stability of complex compounds. For copper(II) complexes with five protonated and deprotonated cyclic oligopeptides containing a disulfide bridge, we developed two common models. The variables used in both models are valence molecular connectivity index of the third order, ³χ^v, and indicator variable(s), In or In₁ and In₂. The model with In₁ and In₂ (they represent the number of terminal and non-terminal glycine residues, respectively) yielded better estimates (S.E._cv?=?0.51) than the model with In (= In₁?+?In₂); S.E._cv?=?0.60.     

Stability prediction of Cu2+, Ni2+ and Zn2+ N-salicylidene-aminoacidato complexes by models based on connectivity index 3 χ v

This paper presents models for the estimation of stability constants (K ₁ and β ₂) of nickel(II), copper(II) and zinc(II) mono- and bis-complexes with 5 Schiff bases (salicylideneglycine, salicylidenealanine, salicylideneserine, salicylidenephenylalanine, and salicylidenetyrosine). The models were based on the molecular-graph theory and valence molecular connectivity index of the 3^rd order, ³χ ^v , derived from it. Univariate linear models were developed for each metal separately, while in the common models for two and three metals, the indicator variable, In, was introduced. The standard error of models for the log K ₁ constant was less than 0.12, while for log β ₂ models, the S.E. did not exceed 0.14.      

Design,synthesis, pharmacological evaluation and in silico ADMET prediction of novel substituted benzimidazole derivatives as angiotensin II–AT1 receptor antagonists based on predictive 3D QSAR models

In this study we designed novel substituted benzimidazole derivatives and predicted their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, based on a predictive 3D QSAR study on 132 substituted benzimidazoles as AngII–AT₁ receptor antagonists. The two best predicted compounds were synthesized and evaluated for AngII–AT₁ receptor antagonism. Three different alignment tools for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used. The best 3D QSAR models were obtained using the rigid body (Distill) alignment method. CoMFA and CoMSIA models were found to be statistically significant with leave-one-out correlation coefficients (q²) of 0.630 and 0.623, respectively, cross-validated coefficients (r²_cv) of 0.651 and 0.630, respectively, and conventional coefficients of determination (r²) of 0.848 and 0.843, respectively. 3D QSAR models were validated using a test set of 24 compounds, giving satisfactory predicted results (r²_pred) of 0.727 and 0.689 for the CoMFA and CoMSIA models, respectively. We have identified some key features in substituted benzimidazole derivatives, such as lipophilicity and H-bonding at the 2- and 5-positions of the benzimidazole nucleus, respectively, for AT₁ receptor antagonistic activity. We designed 20 novel substituted benzimidazole derivatives and predicted their activity. In silico ADMET properties were also predicted for these designed molecules. Finally, the compounds with best predicted activity were synthesized and evaluated for in vitro angiotensin II–AT₁ receptor antagonism.     

Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

Computational Studies and Drug Design for HIV-1 Reverse Transcriptase Inhibitors of 3′,4′-di-O-(S)-camphanoyl-(+)-cis-Khellactone (DCK) Analogs

Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT. Based on the proposed mechanism, some new structures were designed and predicted by a SVM model. All compounds exhibited potent inhibitory activities against HIV replication in H9 lymphocytes with EC50 values lower than 1.95 microM. The rationality of the method was validated by experimental results.     

Computational Screening of 3 d Transition Metal Atoms Anchored on Defective Graphene for Efficient Electrocatalytic N2 Fixation

The synthesis of ammonia (NH₃) through the electrochemical reduction of molecular nitrogen (N₂) is a promising strategy for significantly reducing energy consumption compared to traditional industrial processes. Herein, we report the design of a series of monovacancy and divacancy defective graphenes decorated with single 3d transition metal atoms (TM@MVG and TM@DVG; TM=Sc−Zn) as electrocatalysts for the nitrogen-reduction reaction (NRR) aided by density functional theory (DFT) calculations. By comparing energies for N₂ adsorption as well as the free energies associated with *N₂ activation and *N₂H formation, we successfully identified V@MVG, with the lowest potential of −0.63 V, to be an effective catalytic substrate for the NRR in an enzymatic mechanism. Electronic properties, including Bader charges, charge density differences, partial densities of states, and crystal orbital Hamilton populations, are further analyzed in detail. We believe that these results help to explain recent observations in this field and provide guidance for the exploration of efficient electrocatalysts for the NRR.