Amino Acid Binding Research Articles

Evaluation of the toxicological effects of atrazine-metolachlor in male rats: in vivo and in silico studies.

The types and mechanisms of atrazine-metolachlor toxicity, an herbicide composed of atrazine (ATR) and metolachlor (MET), need to be further investigated. This study evaluated the toxic actions of ATR-MET by in vivo and in silico methods. Here, varying doses of ATR-MET were orally administered to rats once daily for twenty-one days using normal saline as control. Molecular docking was used to characterize the binding of ATR and MET with androgen receptor (AR) to predict their potential endocrine-disrupting effects, using testosterone as benchmark. ATR-MET-induced-testicular toxicity (reduced sperm motility, count, and daily sperm production and increased live/dead ratio) was accompanied with testicular oxidative stress (diminished level of reduced glutathione, activities of glutathione-S-transferase, superoxide dismutase and catalase and increased level of malondialdehyde). Furthermore, ATR-MET induced cardiovascular toxicity (increased levels of plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides) with concomitant induction of renal toxicity (increased plasma creatinine and urea levels), and hepatotoxicity (increased plasma bilirubin, alkaline phosphatase, acid phosphatase, alanine aminotransferase and aspartate aminotransferase). Binding energy and amino acid interactions from in silico study revealed that MET possessed endocrine-disrupting capacity. In conclusion, exposure to atrazine-metolachlor could promote cardiovascular, renal, hepatic, as well as reproductive impairment in experimental male albino rats.

Underutilized legumes, Cajanus cajan and Glycine max may bring about antisickling effect in sickle cell disease by modulation of redox homeostasis in sickled erythrocytes and alteration of its functional chemistry.

The antisickling and anti-oxidative effect of the Cajanus cajan, Glycine max, and their blends were investigated in sickled erythrocytes. The powdered samples were analyzed for their nutritional and anti-nutritional constituents. Their aqueous extracts were analyzed for in vitro antioxidant activities. The extracts were incubated with sickled erythrocytes at 37°C for 6hours and the antisickling effect examined via microscopic analysis. The blend was the most active and its incubated cells were subjected to anti-oxidative analysis which covers for GSH, SOD, catalase, and lipid peroxidation (LPO). Chemical functional group of the treated cells was analyzed with FTIR spectroscopy. The in silico binding of the predominant amino acid to hemoglobin was also investigated. An increased concentration of leucine was observed in the blend compared to that of C. cajan and G. max, respectively. Vitamins C, B6, and B9 were the only vitamins observed in the blend. Phytate and oxalate were present in all samples. All extracts displayed significant (p < .05) scavenging activities. Treatment with the blend exacerbated SOD and catalase activities as well as the GSH level, while suppressing LPO. FTIR analysis of the treated cells showed the presence of hydrophobic functional groups. Leucine was the predominant amino acid, and it showed a potent molecular interaction with HIS-87 residue of the alpha chain of 1HCO. C. cajan and G. max blend inhibited sickling activities of sickle erythrocytes, while concomitantly exacerbating their endogenous antioxidant enzymes activity and modification of the functional chemistry. PRACTICAL APPLICATIONS: Cajanus cajan and Glycine max are among the common underutilized legumes in Nigeria. Aside their nutritional properties, these legumes have been used from time immemorial for the treatment and management of various ailments. Sickle cell anemia is a class of hemoglobinopathy common in Sub-Saharan Africa. There have been concerns about its treatment owing to the increasing scourge of the disease coupled to the financial burden of its management. This study reports the ability of the potentials of the legumes to prevent sickling activities of sickled erythrocytes and the possible biochemical mechanism involved.

Comparing the difference in enhancement of kokumi-tasting γ-glutamyl peptides on basic taste via molecular modeling approaches and sensory evaluation

γ-Glutamyl peptides can enhance basic taste sensations such as saltiness, sweetness, and umaminess, while the molecular mechanism and the difference in taste enhancement remain elusive. Thus, two complex conformations: taste type 1 receptor 1 (T1R1)-MSG and taste type 1 receptor 2 (T1R2)-sucrose were constructed to form binding receptors. These peptides showed affinity for the two receptors, but a higher affinity scores and more binding amino acid residues for the T1R1-MSG receptor, implying that they may exhibit a higher umami-enhancing effect. Thereinto, γ-glutamyl alanine (γ-EA) displayed the highest affinity for the two receptors through mobilizing multiple amino acid residues to form hydrophobic and hydrogen bonds, indicating it had the highest enhancement for umaminess and sweetness among these peptides. Sensory evaluation demonstrated the enhancement of γ-EA on umaminess was superior to that of sweetness. Generally, γ-glutamyl peptides could enhance basic taste sensation via activating taste receptor, and exhibited a highest umami-enhancing effect.

Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine.

Ribosome serves as a universal molecular machine capable of synthesis of all the proteins in a cell. Small-molecule inhibitors, such as ribosome-targeting antibiotics, can compromise the catalytic versatility of the ribosome in a context-dependent fashion, preventing transpeptidation only between particular combinations of substrates. Classic peptidyl transferase center inhibitor chloramphenicol (CHL) fails to inhibit transpeptidation reaction when the incoming A site acceptor substrate is glycine, and the molecular basis for this phenomenon is unknown. Here, we present a set of high-resolution X-ray crystal structures that explain why CHL is unable to inhibit peptide bond formation between the incoming glycyl-tRNA and a nascent peptide that otherwise is conducive to the drug action. Our structures reveal that fully accommodated glycine residue can co-exist in the A site with the ribosome-bound CHL. Moreover, binding of CHL to a ribosome complex carrying glycyl-tRNA does not affect the positions of the reacting substrates, leaving the peptide bond formation reaction unperturbed. These data exemplify how small-molecule inhibitors can reshape the A-site amino acid binding pocket rendering it permissive only for specific amino acid residues and rejective for the other substrates extending our detailed understanding of the modes of action of ribosomal antibiotics.

Structural aspects of triazole derivatives as HSP90 inhibitors for the treatment of cancer: in silico studies

HSP90, one important class of chaperons has been intensively investigated as a promising and novel class of drug target for cancer therapy from the past few decades. A series of 2-((4-resorcinolyl)-5-aryl-1, 2, 3-triazol-1-yl) acetate derivatives were taken in the present study for the generation of pharmacophore based models, predictive 3 D-QSAR models, docking and ZINC screening studies against HSP90. The investigation included 30 ligands which emerged DHRRR_1 having survival score of 5.59 was found the most effective pharmacophore model. The generated third PLS factor includes a model with significant Q2, R2, and R2 CV values as 0.62, 0.77, and 0.50, respectively. The molecular docking studies against HSP90 showed interactions with important amino acids such as GLY-97, ASN-106, THR-184, ASN-51, PHE-138 and SER-52 required for HSP90 inhibitory activity. According to the docking analysis compound 34 was the top scoring compound, had a docking score of −10.98 from the series and showed interactions with amino acids likeASP-93, GLY-97, AND ASP-102. Using pharmacophore characteristics, the virtual screening investigation was carried out and DHRRR_1 showed the potential ZINC compounds. The ZINC compounds ZINC72417069 and ZINC77522480 showed best XP docking scores (-8.205 and −7.103 consecutively) and the top-scoring compound ZINC72417069 displayed amino acid binding affinity with GLY-97, ASN-106, and THR-184 against HSP90, PDB ID: 2xjx. These ZINC compounds can be used as target for HSP90. The result of the study may further help to the scientist for the design and development of potential HSP90 inhibitors.

A single amino acid substitution alters activity and specificity in Plasmodium falciparum aspartyl & asparaginyl-tRNA synthetases

The specificity of each aminoacyl-tRNA synthetase (aaRS) for its cognate amino acid ensures correct tRNA esterification and allows fidelity in protein synthesis. The aaRSs discriminate based on the chemical properties of their amino acid substrates and structural features of the binding pockets. In this study, we characterized aspartyl-(DRS) and asparaginyl-tRNA synthetase (NRS) from Plasmodium falciparum to determine the basis of their specificity towards L-asp and L-asn respectively. The negatively charged L-asp and its analogue L-asn differ only in their side-chain groups i.e., -OH and -NH2. Further, the amino acid binding sites are highly conserved within these two enzymes. Analysis of the substrate (L-asp/L-asn) binding sites across species revealed two highly conserved residues in PfDRS (D408 and K372) and PfNRS (E395 and L360) that are involved in recognition of the Oδ2/Nδ2 of L-asp/L-asn respectively. These residues were mutated and swapped between the D408→E in PfDRS and the corresponding E395→D in PfNRS. A similar approach was employed for residue number K372→L in PfDRS and L360→K in PfNRS. The mutated PfDRSD408E retained its enzymatic activity during step 1 of aminoacylation reaction towards L-asp and L-asn and esterified tRNAAsp with L-asp like wild type enzyme, while the PfDRSK372L was rendered enzymatically inactive. The correspondingly mutated PfNRSE395D was enzymatically inactive. The mutated PfNRSL360K had an altered specificity and esterified tRNAAsn with non-cognate amino acid L-asp and not L-asn. These data suggest that the residue K372 is crucial for the enzymatic activity of PfDRS while the residue L360 in PfNRS imparts specificity towards L-asn.

Determination of amino acids of plants from Angelica L. genus by HPLC method

One of the tasks of pharmaceutical science is to find new sources of effective drugs. Such sources include plants such as Angelica archangelica L. and Angelica sylvestris L., which have been used for many years to treat various diseases in folk medicine. Because the chemical composition of these plants is poorly understood, the aim of our study was to investigate the amino acid composition of the leaves of A. archangelica L. and A. sylvestris L. The amino acids of the leaves of the study species of the genus Angelica L. were determined by the HPLC method. Eighteen free and nineteen bound amino acids were identified in the leaves of A. archangelica L. The A. sylvestris L. leaves contained nineteen free and the same amount of bound amino acids. High concentrations of free and bound amino acids such as L-glutamic acid and L-aspartic acid predominate in A. archangelica L. and A. sylvestris L. This allowed these amino acids to be considered distinguishing markers of the study plants. Character metabolic processes in which these amino acids take part may be associated with the medicinal properties of these plants pursuant to their use in medicine and, therefore, may contribute to the insight of their therapeutic properties.

Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy.

SARS-CoV-2 is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. Because the molecular biology of this virus has been studied in such great detail, it represents an archetypal paradigm for research into new antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis of furin and 3CLpro cleavage sites that augment infection. Non-RBD and non-interfacial mutations assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Kappa, Lambda and Omicron variants, which stabilize the RBD-ACE2 complex, are investigated by free-energy computational approaches, as well as equilibrium and steered molecular dynamic simulations. Considered also are the structural hydropathy traits of the residues in the interface between SARS-CoV-2 RBD and ACE2 protein. Salt bridges and π-π interactions are critical forces that create stronger complexes between the RBD and ACE2. The trend of mutations is the replacement of non-polar hydrophobic interactions with polar hydrophilic interactions, which enhance binding of RBD with ACE2. However, this is not always the case, as conformational landscapes also contribute to a stronger binding. Arginine, the most polar and hydrophilic among the natural amino acids, is the most aggressive mutant amino acid for stronger binding. Arginine blockers, such as traditional sartans that bear anionic tetrazoles and carboxylates, may be ideal candidate drugs for retarding viral infection by weakening S-protein RBD binding to ACE2 and discouraging hydrolysis of cleavage sites. Based on our computational results it is suggested that a new generation of “supersartans”, called “bisartans”, bearing two anionic biphenyl-tetrazole pharmacophores, are superior to carboxylates in terms of their interactions with viral targets, suggesting their potential as drugs in the treatment of COVID-19. In Brief: This in silico study reviews our understanding of molecular driving forces that trigger mutations in the SARS-CoV-2 virus. It also reports further studies on a new class of “supersartans” referred to herein as “bisartans”, bearing two anionic biphenyltetrazole moieties that show potential in models for blocking critical amino acids of mutants, such as arginine, in the Delta variant. Bisartans may also act at other targets essential for viral infection and replication (i.e., ACE2, furin cleavage site and 3CLpro), rendering them potential new drugs for additional experimentation and translation to human clinical trials.

Dynamic gating of substrate binding in β‐amylase2 from Arabidopsis thaliana

β‐Amylases (BAMs) in plants are hydrolases involved in starch degradation, which is important for providing sugar when current photosynthate is unavailable. Plant genomes contain multiple BAM genes some of which have unknown functions. BAM2 in Arabidopsis thaliana is an unusual b‐amylase in that it is tetrameric with sigmoidal kinetics. Other catalytically active BAMs are monomeric with hyperbolic kinetics. A deep groove formed between BAM2 dimers forms a secondary binding site (SBS) for starch and this binding is necessary for activity. To investigate the nature of this catalytic mechanism we aligned BAM2 orthologs with other BAMs and noticed several regions that are uniquely conserved. One of these regions, a surface loop between the active site and the SBS, which we refer to as the HED loop, is three‐amino acids longer in BAM2 than in other BAMs. The loop is proximal to the conserved substrate binding sites suggesting a role for these amino acids in substrate binding. When this loop is shortened, the KM for starch is about 2‐fold lower with a sigmoidal kinetics curve. Using molecular docking, we compared the affinity of WT and mutated BAM2 models for maltose and maltodextrin substrates and found that the mutant shows higher affinities. A second unique site is a Ser residue adjacent to a catalytic Glu that when mutated to Gly, the residue conserved in typical BAMs, results in a 7.5‐fold lower KM for starch. Simulation of the dynamics of BAM2 with the Ser to Gly substitution shows increased tendency for the HED loop to be away from the active site. These data suggest the presence of an active site gate in BAM2 which controls substrate binding and is unique to BAM2.

Calendula officinalis Phytochemicals for the Treatment of Wounds Through Matrix Metalloproteinases-8 and 9 (MMP-8 and MMP-9): In Silico Approach

Diabetic foot ulceration is a common complication of an uncontrolled diabetic regimen and is considered a serious type of wound. Matrix metalloprteinases (MMPs) are the common key enzymes in wound management, overexpression of MMPs can lead to chronic wounds and ulcers. Calendula officinalis extract has established its efficacy in treating wounds in folk medicine. In this research work, we will focus on the chemical constituents of this promising herb and will investigate its abilities to target matrix metalloprteinase-8 (MMP-8) and matrix metalloprteinase-9 (MMP-9) proteins through the usage of computer-aided drug design tools. In the current study, several promising dual inhibitors are identified, such as quercetin, isoquercetin, isorhamnetin, and isorhamnetin 3-O glycoside, they showed to be good inhibitors for both enzyme subtypes with greater docking score energies than RND-336, which has been reported as a selective MMP-9 inhibitor. Binding scores and amino acid interactions in addition to molecular dynamics (MD) will be discussed in detail through this research work.

Effects of oral glutamine supplementation on jejunal morphology, development, and amino acid profiles in male low birth weight suckling piglets.

BackgroundIt has been shown that small intestine development in low birth weight (LBW) piglets is impaired. Glutamine (Gln) has been reported to improve piglet health and intestinal function in weaned piglets, but data is scarce in suckling piglets. This study was conducted to investigate the effects of oral Gln supplementation compared to Alanine (Ala) on jejunal development and function in 5 and 12 d old male LBW and normal birth weight (NBW) suckling piglets.ResultsGln had no effect on the jejunal morphology, development, tissue and digesta amino acid profiles and mRNA abundance of genes involved in amino acid transport, metabolism, glutathione synthesis in LBW piglets when compared to Ala supplementation and birth weight controls at 5 and 12 d. Only the concentration of Gln in jejunal tissue was higher in NBW piglets supplemented with Gln compared to Ala at 5 d (P < 0.05). A comparison of the birth weight groups showed no differences between LBW and NBW piglets at 5 and 12 d in any parameter. Jejunal crypt depth, villus height / width, tunica muscularis thickness, number of goblet and IgA positive cells, the ratio of jejunal RNA to DNA and the concentration of DNA, protein and RNA changed (P < 0.05) from 5 compared to 12 d. The concentrations of several free, and protein bound amino acids as well as amino metabolites differed between age groups in jejunal tissue but the digesta concentrations were affected to a lesser extent.ConclusionsOral Gln supplementation to suckling male piglets over the first 12 d of life was not associated with changes in jejunal parameters measured in this study. The absence of effects may indicate that Gln is absorbed as well as metabolized in the upper intestinal tract and thus could benefit intestinal development at a more proximal location.

Integrated mRNA and Small RNA Sequencing Reveals microRNAs Associated With Xylem Development in Dalbergia odorifera.

Dalbergia odorifera is a rare and precious rosewood specie, whose wood is a very high-quality material for valuable furniture and carving crafts. However, limited information is available about the process of wood formation in D. odorifera. To determine genes that might be closely associated with the xylem differentiation process, we analyzed the differentially expressed genes (DEGs) and microRNAs (miRNAs) from specific xylem tissues of D. odorifera by RNA sequencing (RNA-seq) and small RNA sequencing (small RNA-seq). In total, we obtained 134,221,955 clean reads from RNA-seq and 90,940,761 clean reads from small RNA-seq. By comparing the transition zone (Dotz) and sapwood (Dosw) samples, a total of 395 DEGs were identified. Further analysis revealed that DEGs encoded for WRKY transcription factors (eight genes), lignin synthesis (PER47, COMT, CCR2), cell wall composition (UXS2), gibberellin synthesis (KAO2, GA20OX1), jasmonic acid synthesis (OPR2, CYP74A), and synthesis of flavonoids (PAL2) and terpenoids (CYP71A1). Subsequently, a preliminary analysis by small RNA-seq showed that the expressions of 14 miRNAs (such as miR168a-5p, miR167f-5p, miR167h-5p, miR167e, miR390a, miR156g, novel_52, and novel_9) were significantly different between Dotz and Dosw. Further analysis revealed that the target genes of these differentially expressed miRNAs were enriched in the GO terms “amino acid binding,” “cellulase activity,” and “DNA beta-glucosyltransferase activity”. Further, KEGG pathway annotation showed significant enrichment in “fatty acid elongation” and “biosynthesis of unsaturated fatty acids”. These processes might be participating in the xylem differentiation of D. odorifera. Next, expression correlation analysis showed that nine differentially expressed miRNAs were significantly negatively associated with 21 target genes, which encoded for proteins such as pyrH, SPL6, SPL12, GCS1, and ARF8. Overall, this is the first study on miRNAs and their potential functions in the xylem development of D. odorifera, which provides a stepping stone for a detailed functional investigation of D. odorifera miRNAs.

In sillico binding affinity studies of microbial enzymatic degradation of plastics

Numerous recent research have shown that a variety of microbes and enzymes are capable of decomposing synthetic plastics. To verify the usage of these enzymes in plastic breakdown, in silico investigation of the binding affinity of common plastic compounds [polyamide (PA), poly vinyl chloride (PVC), polycarbonate (PC), polyethylene terephthalate (PET), polymethyl methacrylate (PMMA) and polyurethane (PUR)] to several enzymes such as lipase, carboxylesterase, lignin peroxidase, copper dependent laccase, alkane hydroxylases and manganese peroxidase was conducted. The multiple ligand molecular simulations of the plastic compounds docked on the enzyme targets was done with Autodock Vina in PyRx software version 0.8. Aside from observing for active site interaction between the enzyme-substrates complexes, other parameters such as the highest binding affinity, hydrophobic interactions, and hydrogen bonds were also investigated. Results showed that based on binding affinity, manganese peroxidase showed the best degradation for all plastic types in the order PVC (- 2.7 kcal/mol) < PMMA/PUR (- 4.7 kcal/mol) < PA (-7.5 kcal/mol) < PET (-7.8 kcal/mol) < PC (- 9.1 kcal/mol). The binding amino acid residues mainly include arginine, leucine and serine for all plastics while the interactions involved Van der Waals, conventional hydrogen bonding, carbon-hydrogen bond and Pi- Interactions. Cluster analysis on the basis of their response to enzyme attack showed two cluster groups A and B. Cluster A includes three plastics (PMMA, PUR and PVC), while cluster B also comprises three plastics (PA, PET and PC), suggesting similar degradation pathways. The study demonstrated the potential use of these enzymes for the degradation of plastics.

A small molecule inhibitor of VSIG-8 prevents its binding to VISTA.

The V-region immunoglobulin-containing suppressor of T cell activation (VISTA), a unique B7 family member, is an attractive immunotherapeutic target for cancer, autoimmune and inflammatory diseases. In 2016, a patent demonstrated V-Set and Immunoglobulin domain containing 8 (VSIG-8) was the putative VISTA receptor. Antagonistic or agonistic agents can conceivably modulate VISTA and its interacting partners, which will greatly benefit the treatment of many diseases. The interaction of VISTA and VSIG-8 were measured by Enzyme-linked Immuno Sorbent Assay (ELISA), Microscale Thermophoresis (MST) and coimmunoprecipitation (Co-IP) experiments. The bioactivity of VSIG-8 inhibitor L557-0155 was evaluated in vitro and in vivo. Kd value of human VISTA binding to human VSIG-8 was 1.58 ± 0.44μM by MST. When the related amino acid binding site of VISTA was mutated to alanine, the interaction between VISTA and VSIG-8 disappeared. VSIG-8 protein induced an decrease in the level of IL-2 in VISTA-overexpressing cells but a increase in VISTA-/- cells. Furthermore, VSIG-8 inhibitor L557-0155 promoted cytokine production and cell proliferation in PBMCs and suppressed melanoma growth. VSIG-8/VISTA coinhibitory pathway may provide a novel strategy for the treatment of human cancers, and VSIG-8 blockade may increase antitumor immunity. This study was the first time to report that VSIG-8 interacts with VISTA, and inhibited T cell function.

Directional-path modification strategy enhances PET hydrolase catalysis of plastic degradation

Poly (ethylene terephthalate) (PET) is a widely used type of general plastic that produces a significant amount of waste due to its non-degradable properties. We propose a novel directional-path modification (DPM) strategy, involving positive charge amino acid introduction and binding groove remodeling, and apply it to Thermobifida fusca cutinase to enhance PET degradation. The highest value of PET degradation (90%) was achieved in variant 4Mz (H184S/Q92G/F209I/I213K), exhibiting values almost 30-fold that of the wild-type. We employed molecular docking, molecular dynamics simulations, and QM/MM MD for the degradation process of PET, accompanied by acylation and deacylation. We found that the distance of nucleophilic attack was reduced from about 4.6 Å in the wild type to 3.8 Å in 4Mz, and the free energy barrier of 4Mz dropped from 14.3 kcal/mol to 7.1 kcal/mol at the acylation which was the rate-limiting step. Subsequently, the high efficiency and universality of the DPM strategy were successfully demonstrated in LCC, Est119, and BhrPETase enhancing the degradation activity of PET. Finally, the highest degradation rate of the pretreated commercial plastic bottles had reached to 73%. The present study provides insight into the molecular binding mechanism of PET into the PET hydrolases structure and proposes a novel DPM strategy that will be useful for the engineering of more efficient enzymes for PET degradation.

Identification of phytochemical inhibitors of SARS-CoV-2 protease 3CLpro from selected medicinal plants as per molecular docking, bond energies and amino acid binding energies

Recent worldwide outbreak of SARS-COV-2 pandemic has increased the thirst to discover and introduce antiviral drugs to combat it. The bioactive compounds from plant sources, especially terpenoid have protease inhibition activities so these may be much effective for the control of viral epidemics and may reduce the burden on health care system worldwide. Present study aims the use of terpenoid from selected plant source through bioinformatics tools for the inhibition of SARS-COV-2. This study is based on descriptive analysis. The Protein Data Bank and PubChem database were used for the analysis of SARS-COV-2 protease and plant source terpenoids. Molecular docking by using molegro virtual docker (MVD) software was carried out. The findings of study are based on the inhibitory actions of different plant sourced terpenoid against SARS-COV-2. As per the available resources and complementary analysis these phytochemicals have capacity to inhibit 3CLpro protease. The study reports that (3,3-dimethylally) isoflavone (Glycine max), licoleafol (Glycyrrhiza uralensis), myricitrin (Myrica cerifera), thymoquinone (Nigella sativa), bilobalide, ginkgolide A (Ginkgo biloba), Salvinorin A (Salvia divinorum), citral (Backhousia citriodora) and prephenazine (drug) showed high activity against SARS-COV-2 protease 3CLpro. The drug like and ADMET properties revealed that these compounds can safely be used as drugs. Cross structural analysis by using bioinformatics study concludes that these plant source terpenoid compounds can be effectively used as antiprotease drugs for SARS-COV-2 in future.

Amino Acid Complexes of Zirconium in a Carbon Composite for the Efficient Removal of Fluoride Ions from Water.

Amino acid complexes of zirconia represent an entirely new class of materials that were synthesized and studied for the first time for the decontamination of fluoride ion containing aqueous solutions. Glutamic and aspartic acid complexes of zirconia assembled with thin carbon (stacked graphene oxide) platelets deriving from graphite oxide (GO) were synthesized by a two-step method to prepare adsorbents. The characterization of the complexes was carried out using infrared spectroscopy to determine the functional groups and the types of interaction between the composites and fluoride ions. To reveal the mechanisms and extent of adsorption, two types of batch adsorption measurements were performed: (i) varying equilibrium fluoride ion concentrations to construct adsorption isotherms at pH = 7 in the absence of added electrolytes and (ii) using fixed initial fluoride ion concentrations (10 mg/L) with a variation of either the pH or the concentration of a series of salts that potentially interfere with adsorption. The experimental adsorption isotherms were fitted by three different theoretical isotherm equations, and they are described most appropriately by the two-site Langmuir model for both adsorbents. The adsorption capacities of Zr-glutamic acid-graphite oxide and Zr-aspartic acid-graphite oxide are 105.3 and 101.0 mg/g, respectively. We found that two distinct binding modes are combined in the Zr-amino acid complexes: at low solution concentrations, F− ions are preferentially adsorbed by coordinating to the surface Zr species up to a capacity of ca. 10 mg/g. At higher concentrations, however, large amounts of fluoride ions may undergo anion exchange processes and physisorption may occur on the positively charged ammonium moieties of the interfacially bound amino acid molecules. The high adsorption capacity and affinity of the studied dicarboxylate-type amino acids demonstrate that amino acid complexes of zirconia are highly variable materials for the safe and efficient capture of strong Lewis base-type ions such as fluoride.

Binary and Ternary Complexes of Cucurbit[8]uril with Tryptophan, Phenylalanine, and Tyrosine: A Computational Study.

Selective binding of amino acids, peptides, and proteins by synthetic molecules and elucidation of the geometry and dynamics of the resulting complexes and their strengths are active areas of contemporary research. In recent work, we analyzed via molecular dynamics (MD) simulations the complexes formed between cucurbit[7]uril (CB7) and three aromatic amino acids: tryptophan (W), phenylalanine (F), and tyrosine (Y). Herein, we continue this line of research by performing MD simulations lasting 100 ns to investigate the formation, stabilities, binding modes, dynamics, and specific host–guest noncovalent interactions contributing to the formation of the binary (1:1) and ternary (2:1) complexes in aqueous solution between W, F, and Y amino acids and cucurbit[8]uril (CB8). All complexes were found to be stable, with the binding in each complex dominated by one mode (except for the F–CB8 complex, which had two) characterized by encapsulation of the aromatic side chains of the amino acids within the cavity of CB8 and the exclusion of their ammonium and carboxylate groups. Using the molecular mechanics/Poisson–Boltzmann surface area method to estimate the individual contributions to the overall free energies of binding, results revealed that the key role is played by the amino acid side chains in stabilizing the complexes through their favorable van der Waals interactions with the CB8 cavity and the importance of favorable electrostatic interactions between the carbonyl portal of CB8 and the ammonium group of the amino acid. Visual analysis of structures of the ternary complexes indicated the presence of π–π stacking between the aromatic side chains of the included amino acids. The insights provided by this work may be of value for further efforts aiming to employ the recognition properties of CB8 toward amino acids in applications requiring more elaborate recognition of short peptides and proteins.

Multitarget-Based Virtual Screening for Identification of Herbal Substances toward Potential Osteoclastic Targets

Osteoporosis is a complex bone disease indicating porous bone with low bone mass density and fragility. Cathepsin K, V-ATPase, and αVβ3 integrin are exhibited as novel targets for osteoporosis treatment. Our preliminary study uses a state-of-the-art method, including target-based virtual screening and clustering methods to determine promising candidates with multitarget properties. Phytochemicals with osteoprotective properties from the literature are used to elucidate the molecular interactions toward three targets. The binding scores of compounds are normalized and rescored. The K-means and hierarchical clustering methods are applied to filter and define the promising compounds, and the silhouette analysis is supposed to validate the clustering method. We explore 108 herbal compounds by virtual screening and the cluster approach, and find that rutin, sagittatoside A, icariin, and kaempferitrin showed strong binding affinities against Cathepsin K, V-ATPase, and αVβ3 integrin. Dockings of candidates toward three targets also provide the protein-ligand interactions and crucial amino acids for binding. Our study provides a straightforward and less time-consuming approach to exploring the new multitarget candidates for further investigations, using a combination of in silico methods.

Amino acid sensor conserved from bacteria to humans

SignificanceAmino acids are the building blocks of life and important signaling molecules. Despite their common structure, no universal mechanism for amino acid recognition by cellular receptors is currently known. We discovered a simple motif, which binds amino acids in various receptor proteins from all major life-forms. In humans, this motif is found in subunits of calcium channels that are implicated in pain and neurodevelopmental disorders. Our findings suggest that γ-aminobutyric acid-derived drugs bind to the same motif in human proteins that binds natural ligands in bacterial receptors, thus enabling future improvement of important drugs.