Mechanistic insights into the selectivity of bicyclophosphorothionate antagonists for housefly versus rat GABA receptors.

BACKGROUND: γ-Aminobutyric acid (GABA) receptors (GABARs) are validated targets of insecticides. Bicyclophosphorothionates are a group of insecticidal compounds that act as noncompetitive antagonists of GABARs. We previously reported that the analogs exhibit various degrees of selectivity for housefly versus rat GABARs, depending on substitutions at the 3- and 4-positions. We here sought to elucidate the unsolved mechanisms of the receptor selectivity using quantitative structure-activity relationship (QSAR), molecular docking, and molecular dynamics approaches. RESULTS: Three-dimensional (3D)-QSAR studies using Topomer comparative molecular field analysis quantitatively demonstrated how the introduction of a small alkyl group at the 3-position of bicyclophosphorothionates contributes to the housefly versus rat GABAR selectivity. To investigate the molecular mechanisms of the selective action, bicyclophosphorothionates were docked into housefly Resistance to dieldrin (RDL) GABAR and rat α1ß2γ2 GABAR homology models built using the published 3D-structures of human GABARs as templates. The results of molecular docking and molecular dynamics simulations revealed that the 2'Ala and 6'Thr residues of the RDL subunit within the channel are the key amino acids for binding to the housefly GABARs, whereas the 2'Ser residue of γ2 subunit plays a crucial role in binding to rat GABARs. CONCLUSION: We revealed the molecular mechanisms underlying the selective antagonistic action of bicyclophosphorothionates on housefly versus rat GABARs. The information presented should help design and develop novel, safe GABAR-targeting insecticides. © 2023 Society of Chemical Industry.

Exploration of N-Arylsulfonyl-indole-2-carboxamide Derivatives as Novel Fructose-1,6-bisphosphatase Inhibitors by Molecular Simulation.

A series of N-arylsulfonyl-indole-2-carboxamide derivatives have been identified as potent fructose-1,6-bisphosphatase (FBPase) inhibitors (FBPIs) with excellent selectivity for the potential therapy of type II diabetes mellitus. To explore the structure-activity relationships (SARs) and the mechanisms of action of these FBPIs, a systematic computational study was performed in the present study, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, pharmacophore modeling, molecular dynamics (MD), and virtual screening. The constructed 3D-QSAR models exhibited good predictive ability with reasonable parameters using comparative molecular field analysis (q2 = 0.709, R2 = 0.979, rpre2 = 0.932) and comparative molecular similarity indices analysis (q2 = 0.716, R2 = 0.978, rpre2 = 0.890). Twelve hit compounds were obtained by virtual screening using the best pharmacophore model in combination with molecular dockings. Three compounds with relatively higher docking scores and better ADME properties were then selected for further studies by docking and MD analyses. The docking results revealed that the amino acid residues Met18, Gly21, Gly26, Leu30, and Thr31 at the binding site were of great importance for the effective bindings of these FBPIs. The MD results indicated that the screened compounds VS01 and VS02 could bind with FBPase stably as its cognate ligand in dynamic conditions. This work identified several potential FBPIs by modeling studies and might provide important insights into developing novel FBPIs.

5-(4-Pyridinyl)-3-isothiazolols as Competitive Antagonists of Insect GABA Receptors: Design, Synthesis, and a New Mechanism Leading to Insecticidal Effects.

Ionotropic γ-aminobutyric acid (GABA) receptors (iGABARs) are validated targets of drugs and insecticides. Our previous studies showed that the competitive antagonists of insect iGABARs exhibit insecticidal activities and that the 3-isothiazolol scaffold is used as a lead for developing novel iGABAR antagonists. Here, we designed a novel series of 4-aryl-5-(4-pyridinyl)-3-isothiazolol (4-API) analogs that have various aromatic substituents at the 4-position. Two-electrode voltage clamp experiments showed that all synthesized 4-APIs exhibited antagonistic activity against Musca domestica and Spodoptera litura iGABARs (RDL) expressed in oocytes of Xenopus laevis at 100 µM. Of the 4-APIs, the 4-(1,1'-biphenylyl) analog was the most potent antagonist with IC50s of 7.1 and 9.9 µM against M. domestica and S. litura RDL receptors, respectively. This analog also showed a certain insecticidal activity against S. litura larvae, with >75% mortality at 100 µg/g diet. Molecular docking studies with a M. domestica iGABAR model indicated that the π-π stacking interactions formed between the pyridinyl ring and Y252 and between the 4-substituted aromatic group and Y107 might be important for antagonism by the 4-(1,1'-biphenylyl) analog. Our studies provide important information for designing novel iGABAR antagonists and suggest that the 4-APIs acting on iGABARs are promising insecticide leads for further studies.

Novel insecticidal 1,6-dihydro-6-iminopyridazine derivatives as competitive antagonists of insect RDL GABA receptors.

BACKGROUND: The ionotropic γ-aminobutyric acid (GABA) receptor (iGABAR) is an important target for insecticides and parasiticides. Our previous studies showed that competitive antagonists (CAs) of insect iGABARs have the potential to be used for developing novel insecticides and that the structural modification of gabazine (a representative CA of mammalian iGABARs) could lead to the identification of novel CAs of insect iGABARs. RESULTS: In the present study, a novel series of 1,3-di- and 1,3,5-trisubstituted 1,6-dihydro-6-iminopyridazines (DIPs) was designed using a versatile strategy and synthesized using facile methods. Electrophysiological studies showed that several target DIPs (30 µM) exhibited excellent antagonistic activities against common cutworm and housefly iGABARs consisting of RDL subunits. The IC50 values of 3-(4-methoxyphenyl), 3-(4-trifluoromethoxyphenyl), 3-(4-biphenylylphenyl), 3-(2-naphthyl), 3-(3,4-methylenedioxyphenyl), and 3,5-(4-methoxyphenyl) analogs ranged from 2.2 to 24.8 µM. Additionally, several 1,3-disubstituted DIPs, especially 3-(4-trifluoromethoxyphenyl) and 3-(3,4-methylenedioxyphenyl) analogs, exhibited moderate insecticidal activity against common cutworm larvae, with >60% mortality at a concentration of 100 mg kg-1 . Molecular docking studies showed that the oxygen atom on the three-substituted aromatic ring could form a hydrogen bond with Arg254, which may enhance the activity of these DIPs against housefly iGABARs. CONCLUSION: This systematic study indicated that the presence of a carboxyl side chain shorter by one methylene than that of gabazine at the 1-position of the pyridazine ring is effective for maintaining the stable binding of these DIPs in insect iGABARs. Our study provides important information for the design of novel insect iGABAR CAs. © 2022 Society of Chemical Industry.

In Silico Screening of Novel α1-GABAA Receptor PAMs towards Schizophrenia Based on Combined Modeling Studies of Imidazo [1,2-a]-Pyridines.

The ionotropic GABAA receptor (GABAAR) has been proven to be an important target of atypical antipsychotics. A novel series of imidazo [1,2-a]-pyridine derivatives, as selective positive allosteric modulators (PAMs) of α1-containing GABAARs with potent antipsychotic activities, have been reported recently. To better clarify the pharmacological essentiality of these PAMs and explore novel antipsychotics hits, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) were performed on 33 imidazo [1,2-a]-pyridines. The constructed 3D-QSAR models exhibited good predictive abilities. The dockings results and MD simulations demonstrated that hydrogen bonds, π-π stackings, and hydrophobic interactions play essential roles in the binding of these novel PAMs in the GABAAR binding pocket. Four hit compounds (DS01-04) were then screened out by the combination of the constructed models and computations, including the pharmacophore model, Topomer Search, molecular dockings, ADME/T predictions, and MD simulations. The compounds DS03 and DS04, with higher docking scores and better predicted activities, were also found to be relatively stable in the binding pocket by MD simulations. These results might provide a significant theoretical direction or information for the rational design and development of novel α1-GABAAR PAMs with antipsychotic activities.

Exploration of Novel Xanthine Oxidase Inhibitors Based on 1,6-Dihydropyrimidine-5-Carboxylic Acids by an Integrated in Silico Study.

Xanthine oxidase (XO) is an important target for the effective treatment of hyperuricemia-associated diseases. A series of novel 2-substituted 6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (ODCs) as XO inhibitors (XOIs) with remarkable activities have been reported recently. To better understand the key pharmacological characteristics of these XOIs and explore more hit compounds, in the present study, the three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) studies were performed on 46 ODCs. The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters, including q2 = 0.897, R2 = 0.983, rpred2 = 0.948 in a CoMFA model, and q2 = 0.922, R2 = 0.990, rpred2 = 0.840 in a CoMSIA model. Docking and MD simulations further gave insights into the binding modes of these ODCs with the XO protein. The results indicated that key residues Glu802, Arg880, Asn768, Thr1010, Phe914, and Phe1009 could interact with ODCs by hydrogen bonds, π-π stackings, or hydrophobic interactions, which might be significant for the activity of these XOIs. Four potential hits were virtually screened out using the constructed pharmacophore model in combination with molecular dockings and ADME predictions. The four hits were also found to be relatively stable in the binding pocket by MD simulations. The results in this study might provide effective information for the design and development of novel XOIs.

Advances in Research on Anticancer Properties of Salidroside.

Salidroside is a phenolic secondary metabolite present in plants of the genus Rhodiola, and studies investigating its extensive pharmacological activities and mechanisms have recently attracted increasing attention. This review summarizes the progress of recent research on the antiproliferative activities of salidroside and its effects on breast, ovarian, cervical, colorectal, lung, liver, gastric, bladder, renal, and skin cancer as well as gliomas and fibrosarcomas. Thus, it provides a reference for the further development and utilization of salidroside.

Exploring the Interaction Mechanism of Desmethyl-broflanilide in Insect GABA Receptors and Screening Potential Antagonists by In Silico Simulations.

Broflanilide, a novel insecticide, is classified as a negative allosteric modulator (NAM) of insect γ-aminobutyric acid (GABA) receptors (GABARs) as desmethyl-broflanilide (DMBF) allosterically inhibits the GABA-induced responses. The G277M mutation of the Drosophila melanogaster GABAR subunit has been reported to abolish the inhibitory activity of DMBF. The binding mode of DMBF in insect GABARs needs to be clarified to understand the underlying mechanism of this mutation and to develop novel, efficient NAMs of insect GABARs. Here, we found that a hydrogen bond formed between DMBF and G277 of the D. melanogaster GABAR model might be the key interaction for the antagonism of DMBF by in silico simulations. The volume increase induced by the G277M mutation blocks the entrance of the binding pocket, making it difficult for DMBF to enter the binding pocket and thereby decreasing its activity. The following virtual screening and bioassay results identified a novel NAM candidate of insect GABARs. Overall, we reported a possible binding mode of DMBF in insect GABARs and proposed the insensitivity mechanism of the G277M mutant GABAR to DMBF using molecular simulations. The identified NAM candidates might provide more alternatives or potentials for the design of GABAR-targeting insecticides.

Inhibitory effects of salidroside on MCF-7 breast cancer cells in vivo.

OBJECTIVE: We investigated the antitumor effects of salidroside and preliminarily examined its underlying mechanisms by establishing a nude mouse model bearing MCF-7 breast cancer cell xenografts. METHODS: The mice were grouped and intraperitoneally injected with salidroside, paclitaxel, or physiological saline. Tumor samples were weighed, and immunohistochemical staining with hematoxylin and eosin and anti-CD34 antibody was performed. Tumor cell apoptosis was observed using the terminal deoxynucleotidyl transferase deoxyuridine dUTP nick end labeling assay. Bcl-1, p53, Bax, and caspase 3 expression in tumor tissues was determined via western blotting. RESULTS: The tumor inhibition rate of high-dose salidroside was 75.16%, which was significantly higher than the rates for paclitaxel and saline. A tumor tissue pathology analysis revealed that high-dose salidroside inhibited tumor cell proliferation and promoted tumor cell apoptosis. Western blotting revealed that Bcl-2 and p53 expression were significantly lower in the salidroside group than in the other groups, whereas Bax and caspase 3 (17 kDa) expression were increased. CONCLUSIONS: Salidroside was more effective than paclitaxel in inhibiting tumor growth in MCF-7 breast cancer cell-bearing nude mice. The mechanism of action may involve Bcl-2 and p53 downregulation and Bax and caspase 3 upregulation, thereby increasing proapoptotic factor expression and inducing tumor cell apoptosis.

Potential of Competitive Antagonists of Insect Ionotropic γ-Aminobutyric Acid Receptors as Insecticides.

Ionotropic γ-aminobutyric acid (GABA) receptors (GABARs) represent an important insecticide target. Currently used GABAR-targeting insecticides are non-competitive antagonists (NCAs) of these receptors. Recent studies have demonstrated that competitive antagonists (CAs) of GABARs have functions of inhibiting insect GABARs similar to NCAs and that they also exhibit insecticidal activity. CAs have different binding sites and different mechanisms of action compared to those of NCAs. Therefore, GABAR CAs should have the potential to be developed into novel insecticides, which could be used to overcome the developed resistance of insect pests to conventional NCA insecticides. Although research on insect GABAR CAs has lagged behind that on mammalian GABAR CAs, research on the CAs of insect ionotropic GABARs has made great progress in recent years, and several series of heterocyclic compounds, such as 3-isoxazolols and 6-iminopyridazines, have been identified as insect GABAR CAs. In this review, we briefly summarize the design strategies, structures, and biological activities of the novel GABAR CAs that have been found in the past decade. Updated information about GABAR CAs may benefit the design and development of novel GABAR-targeting insecticides.

In silico Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines.

A novel series of dihydrofuro[3,4-d]pyrimidine (DHPY) analogs have recently been recognized as promising HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with potent antiviral activity. To better understand the pharmacological essentiality of these DHPYs and design novel NNRTI leads, in this work, a systematic in silico study was performed on 52 DHPYs using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, virtual screening, absorption-distribution-metabolism-excretion (ADME) prediction, and molecular dynamics (MD) methods. The generated 3D-QSAR models exhibited satisfactory parameters of internal validation and well-externally predictive capacity, for instance, the q2, R2, and r pred 2 of the optimal comparative molecular similarity indices analysis model were 0.647, 0.970, and 0.751, respectively. The docking results indicated that residues Lys101, Tyr181, Tyr188, Trp229, and Phe227 played important roles for the DHPY binding. Nine lead compounds were obtained by the virtual screening based on the docking and pharmacophore model, and three new compounds with higher docking scores and better ADME properties were subsequently designed based on the screening and 3D-QSAR results. The MD simulation studies further demonstrated that the newly designed compounds could stably bind with the HIV-1 RT. These hit compounds were supposed to be novel potential anti-HIV-1 inhibitors, and these findings could provide significant information for designing and developing novel HIV-1 NNRTIs.

A NMR-based drug screening strategy for discovering active substances from herbal medicines: Using Radix Polygoni Multiflori as example.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal medicines have always been important sources for new drugs. And developing new drugs from traditional herbal medicine is currently still an effective way. However, screening for active substances from herbal medicines extracts has ever been a challenging topic, due to their intrinsic complexity. The herb Radix Polygoni Multiflori has been used as a tonic and an antiaging herb in Traditional Chinese Medicine. In clinical studies, the extract of Radix Polygoni Multiflori can improve hypercholesterolemia, atherosclerotic, diabetes and other diseases commonly associated with glycolipid metabolism, however, the molecular mechanisms of these actions are unknown. AIM OF THE STUDY: We devised a NMR-based drug screening strategy for discovering active substances from herbal medicines, using Radix Polygoni Multiflori as example to address such challenging topic, meanwhile, to explore molecular target of Radix Polygoni Multiflori's glycolipid metabolism benefit. MATERIALS AND METHODS: Herbal medicines extracts were subjected to moderate separation to generate libraries of pre-purified subfractions, target protein was then added to each subfraction, and ligand-observed NMR experiments (line-broadening experiment, chemical shift perturbations measurements and saturation transfer difference spectrum) were performed, active substances identification and structural optimization were then accomplished using signals provided by ligand-observed NMR interaction detection and HPLC-SPE-NMR. The strategy was demonstrated by discovering an active component from extract of herb Radix Polygoni Multiflori, using human fatty acid binding protein 4 (FABP4) as target protein. RESULTS: 2,4-dihydroxy-6-[(1E)-2-(4-hydroxyphenyl)ethenyl]phenyl-ß-D-glucopyranoside(TSG), the hit from one subfraction, has obvious interaction with target protein FABP4, due to FABP4 is a potential therapeutic target for metabolic diseases such as diabetes and atherosclerosis, the screening result will give clue to the active component and molecular target of Radix Polygoni Multiflori's glycolipid metabolism benefit. Besides, interaction information at atom level offered by ligand-observed NMR experiment would be valuable in the further stage of lead optimization. CONCLUSIONS: The devised NMR-based drug screening strategy can discover active substances from herbal medicines efficiently and precisely, meanwhile, can shed light on molecular mechanism of traditional usage of the herb.

Identification of The Fipronil Resistance Associated Mutations in Nilaparvata lugens GABA Receptors by Molecular Modeling.

Fipronil, as the first commercialized member of phenylpyrazole insecticides, has been widely used to control planthoppers in China due to its high insecticidal activity and low toxicity to mammals. However, insects have developed resistance to phenylpyrazoles after their long-term use. The resistance mechanism of insects to fipronil has not been well identified, which limited the development of phenylpyrazole insecticides. In the present study, we aimed to elucidate the related fipronil-resistance mechanism in N. lugens GABA receptors by homology modeling, molecular docking, and molecular dynamics. The results indicated that fipronil showed the weakest interaction with the mutant (R0'Q + A2'S) GABA receptors, which is consistent with the experimental study. The binding poses of fipronil were found to be changed when mutations were conducted. These findings verified the novel fipronil-resistance mechanism in silico and provide important information for the design of novel GABAR-targeting insecticides.

Structure characterization and optical properties investigation of the four main components of the classical phenazinium dye Safranin O.

Safranin O is an important and classical phenazinium dye; since the 19th century, it has been extensively used in the academic field as a spectroscopic probe and indicator. Surprisingly, we found that this long-used reagent is without exception a mixture. In this study, the four main components in a Safranin O sample were prepared, and their chemical structures were elucidated for the first time. Optical property investigations showed that the components had somewhat different absorbance properties and markedly different fluorescence properties, and their structure-optical activity relationships were also discussed. It could be inferred that the variation of each component in the content would unavoidably result in inconsistent optical data when using this Safranin O reagent as a spectroscopic probe or indicator. Considering the accurate transfer of measurement results between laboratories, high-purity Safranin O is in urgent demand in the academic field.

Conformational study on telaprevir by HPLC-DAD-MS and theoretical calculation.

Telaprevir is a potent, selective, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3-4A serine protease. it is used for the treatment of HCV infection in combination with peginterferon alfa and ribavirin. In the present work, the E-Z isomerization process of telaprevir in solution was revealed by online HPLC-DAD (diode array detector)-MS, variable-temperature and variable-gradient experiments. The molecular geometry information of the two isomers was established by molecular mechanics calculations, and good correlation between the two isomers' UV-vis spectra and their molecular geometry information was also discovered. In addition, it was revealed by molecular docking that the two isomers have different affinities to HCV NS3•4A protease, and the Z isomer, the minor form of telaprevir in solution, is the more effective inhibitor of HCV NS3•4A protease. The investigation can provide more structure information about telaprevir in solution and in the binding process of HCV NS3•4A protease.

4-Aryl-5-carbamoyl-3-isoxazolols as competitive antagonists of insect GABA receptors: Synthesis, biological activity, and molecular docking studies.

Competitive antagonists (CAs) of ionotropic GABA receptors (GABARs) reportedly exhibit insecticidal activity and have potential for development as novel insecticides for overcoming emerging resistance to traditional GABAR-targeting insecticides. Our previous studies demonstrated that 4,5-disubstituted 3-isoxazolols or 3-isothiazolols are an important class of insect GABAR CAs. In the present study, we synthesized a series of 4-aryl-5-carbamoyl-3-isoxazolols and examined their antagonism of insect GABARs expressed in Xenopus oocytes. Several of these 3-isoxazolols exhibited potent antagonistic activities against housefly and common cutworm GABARs, with IC50 values in the low-micromolar range in both receptors. 4-(3-Amino-4-methylphenyl)-5-carbamoyl-3-isoxazolol (3u) displayed the highest antagonism, with IC50 values of 2.0 and 0.9 µM in housefly and common cutworm GABARs, respectively. Most of the synthesized 3-isoxazolols showed moderate larvicidal activities against common cutworms, with more than 50% mortality at 100 µg/g. These results indicate that 4-monocyclic aryl-5-carbamoyl-3-isoxazolol is a promising scaffold for insect GABAR CA discovery and provide important information for the design and development of GABAR-targeting insecticides with a novel mode of action.

Docking-based 3D-QSAR and pharmacophore studies on diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Diarylpyrimidines (DAPYs), a type of effective HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been considered as one of the most successful agents for treating AIDS. A number of structurally diverse DAPYs have been designed and synthesized in the past decade, and most of them exhibited potent anti-HIV-1 activities; however, the structure-activity relationships of recently reported DAPYs and their pharmacophore features that interacted with HIV-1 reverse transcriptase (RT) remain to be studied. In the present study, molecular docking studies were first performed on three novel classes of DAPYs to study their binding pattern in the HIV-1 RT. Based on the docking conformations of these DAPYs, 3D-QSAR models were constructed using CoMSIA and Topomer CoMFA methods, and pharmacophore models were also built using distance comparison technique. All selected DAPYs presented preferred U- or L-shaped conformations while being docked into the non-nucleoside inhibitor-binding pocket of the HIV-1 RT. The best CoMSIA model exhibited powerful predictivity, with satisfactory statistical parameters such as a q2 of 0.572, an r2 of 0.952, and an [Formula: see text] of 0.728. Contour maps of the best CoMSIA model were in accordance with those of the Topomer CoMFA model, giving the insight into the feature requirements of DAPYs for the anti-HIV-1 activity. Three potential pharmacophore models were constructed, and each of them was consisted of five hypothesis features. All results suggested that the aromatic ring on the left wing of DAPYs and the central pyrimidine ring contained key pharmacophore features for the anti-HIV-1 activity, and also indicated that the right wing of DAPYs had potential for further structural modification to improve activity. Eight novel DAPY molecules with potential anti-HIV-1 activities were designed on the basis of the obtained results. The findings in this study might provide important information for further design and development of novel HIV-1 NNRTIs.

Investigation of serum amino acids involved in gallic acid detoxification of formaldehyde by liquid chromatography/tandem mass spectrometry and neutral loss scan.

RATIONALE: Gallic acid is one of the most common polyphenols in natural products and human diet. The consumption of gallic acid reduces the incidence of cardiovascular diseases, chronic metabolic disorders and cancers. Most previous publications focused on the antioxidative or prooxidative properties of gallic acid. In the present work, gallic acid as a trapping agent of blood formaldehyde was investigated by liquid chromatography/tandem mass spectrometry (LC/MS/MS) and neutral loss scan. METHODS: Serum samples incubated with gallic acid were subjected to LC/MS/MS analysis using an LTQ XL ion trap mass spectrometer. The adduct ions of gallic acid-formaldehyde-amino acids were explored by investigation of their fragmentation patterns and neutral loss scan experiments. RESULTS: A series of Mannich adducts (namely, gallic acid-formaldehyde-alanine, gallic acid-formaldehyde-proline, gallic acid-formaldehyde-leucine or gallic acid-formaldehyde-isoleucine and gallic acid-formaldehyde-phenylalanine) were identified as metabolites by neutral loss scan experiments. CONCLUSIONS: This work demonstrated that serum amino acids are involved in gallic acid detoxification of formaldehyde. Because excessive formaldehyde in blood is implicated in a variety of disease pathologies, detoxification of formaldehyde, especially endogenous formaldehyde, may be another health beneficial effect of gallic acid. It also suggested that more attention should be paid to Mannich-type metabolites of polyphenol-formaldehyde-amino acids in research into the pharmacokinetics and bioavailability of polyphenols.

Advances in diarylpyrimidines and related analogues as HIV-1 nonnucleoside reverse transcriptase inhibitors.

HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.

Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors.

Diarylpyrimidines (DAPYs), acting as HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered to be one of the most potent drug families in the fight against acquired immunodeficiency syndrome (AIDS). To better understand the structural requirements of HIV-1 NNRTIs, three-dimensional quantitative structure⁻activity relationship (3D-QSAR), pharmacophore, and molecular docking studies were performed on 52 DAPY analogues that were synthesized in our previous studies. The internal and external validation parameters indicated that the generated 3D-QSAR models, including comparative molecular field analysis (CoMFA, q 2 = 0.679, R 2 = 0.983, and r pred 2 = 0.884) and comparative molecular similarity indices analysis (CoMSIA, q 2 = 0.734, R 2 = 0.985, and r pred 2 = 0.891), exhibited good predictive abilities and significant statistical reliability. The docking results demonstrated that the phenyl ring at the C4-position of the pyrimidine ring was better than the cycloalkanes for the activity, as the phenyl group was able to participate in π⁻π stacking interactions with the aromatic residues of the binding site, whereas the cycloalkanes were not. The pharmacophore model and 3D-QSAR contour maps provided significant insights into the key structural features of DAPYs that were responsible for the activity. On the basis of the obtained information, a series of novel DAPY analogues of HIV-1 NNRTIs with potentially higher predicted activity was designed. This work might provide useful information for guiding the rational design of potential HIV-1 NNRTI DAPYs.