Towards a better understanding of commonly used medicinal plants from Turkiye: Detailed phytochemical screening and biological activity studies of two Teucrium L. species with in vitro and in silico approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Since ancient times, Teucrium L. species have been among the most commonly used traditional medicinal plants mainly in the Mediterranean region. From tackling gastrointestinal problems to maintaining the healthy functioning of endocrine glands, and from treating malaria to severe dermatological disorders, Teucrium species are known to have extensive therapeutic applications. Teucrium polium L. and Teucrium parviflorum Schreb. are the two members of the genus that have been used in Turkish folk medicine for various medicinal purposes. AIM OF THE STUDY: To determine the phytochemical compositions of the essential oils and ethanol extracts of Teucrium polium and Teucrium parviflorum collected from different locations in Turkiye along with the investigation of in vitro antioxidant, anticancer, antimicrobial activities, and both in vitro and in silico enzyme inhibitory activities of the extracts. MATERIALS AND METHODS: Ethanol extracts of Teucrium polium aerial parts and roots, and aerial parts of Teucrium parviflorum were prepared. Volatile profiling of the essential oils by GC-MS, phytochemical profiling of the ethanol extracts by LC-HRMS, antioxidant activity by DPPH radical scavenging, ABTS cation radical scavenging, CUPRAC, and metal chelating activity assays, anticholinesterase, antityrosinase, antiurease, activities by different enzyme inhibitory activity assays, anticancer activity by SRB cell viability assay, and antimicrobial activity against a standard panel of bacteria and fungi by the microbroth dilution technique. Molecular docking studies were performed by Autodock Vina (Ver. 1.1.2). RESULTS: The studied extracts were found to be quite rich in various biologically important volatile and phenolic compounds. (-)-Epigallocatechin gallate, which is a molecule renowned for having great therapeutic potential, was the major compound of all extracts. Teucrium polium aerial parts extract was revealed as a great source for naringenin with 16327 ± 685.23 µg/g extract. All extracts exerted significant antioxidant activity by different methods. All extracts demonstrated antibutrylcholinesterase, antityrosinase, and antiurease activities by in vitro and in silico assays. Teucrium polium roots extract stood out with remarkable tyrosinase and urease inhibitory and cytotoxic activities. CONCLUSION: The obtained results from this multi-disciplinary study proves that the traditional use of these two Teucrium species is justified, and the mechanisms behind are enlightened.

Designing new drug candidates as inhibitors against wild and mutant type neuraminidases: molecular docking, molecular dynamics and binding free energy calculations.

Influenza virus is the cause of the death of millions of people with about 3-4 pandemics every hundred years in history. It also turns into a seasonal disease, bringing about approximately 5-15% of the population to be infected and 290,000-650,000 people to die every year. These numbers reveal that it is necessary to be on the alert to work towards influenza in order to protect public health. There are FDA-approved antiviral drugs such as oseltamivir and zanamivir recommended by the World Center for Disease Prevention. However, after the recent outbreaks such as bird flu and swine flu, increasing studies have shown that the flu virus has gained resistance to these drugs. So, there is an urgent need to find new drugs effective against this virus. This study aims to investigate new drug candidates targeting neuraminidase (NA) for the treatment of influenza by using computer aided drug design approaches. They involve virtual scanning, de novo design, rational design, docking, MD, MMGB/PBSA. The investigation includes H1N1, H5N1, H2N2 and H3N2 neuraminidase proteins and their mutant variants possessing resistance to FDA-approved drugs. Virtual screening consists of approximately 30 thousand molecules while de novo and rational designs produced over a hundred molecules. These approaches produced three lead molecules with binding energies for both non-mutant (-34.84, -59.99 and -60.66 kcal/mol) and mutant (-40.40, -58.93, -76.19 kcal/mol) H2N2 NA calculated by MM-PBSA compared with those of oseltamivir -25.64 and -18.40 respectively. The results offer new drug candidates against influenza infection.Communicated by Ramaswamy H. Sarma.

Investigation of angucycline compounds as potential drug candidates against SARS Cov-2 main protease using docking and molecular dynamic approaches.

The emerged Coronavirus disease (COVID-19) causes severe or even fatal respiratory tract infection, and to date there is no FDA-approved therapeutics or effective treatment available to effectively combat this viral infection. This urgent situation is an attractive research area in the field of drug design and development. One of the most important targets of SARS-coronavirus-2 (SARS Cov-2) is the main protease (3CLpro). Actinomycetes are important resources for drug discovery. The angucylines that are mainly produced by Streptomyces genus of actinomycetes exhibit a broad range of biological activities such as anticancer, antibacterial and antiviral. This study aims to investigate the binding affinity and molecular interactions of 157 available angucycline compounds with 3CLpro using docking and molecular dynamics simulations. MM-PBSA calculations showed that moromycin A has a better binding energy (- 30.42 kcal mol-1) compared with other ligands (in a range of - 18.66 to - 22.89 kcal mol-1) including saquayamycin K4 (- 21.27 kcal mol-1) except the co-crystallized ligand N3. However, in vitro and in vivo studies are essential to assess the effectiveness of angucycline compounds against coronavirus.

Magnetite nanoparticles grafted with murexide-terminated polyamidoamine dendrimers for removal of lead (II) from aqueous solution: synthesis, characterization, adsorption and antimicrobial activity studies.

In this study, new, efficient, eco-friendly and magnetically separable nanoadsorbents, MNPs-G1-Mu and MNPs-G2-Mu, were successfully prepared by covalently grafting murexide-terminated polyamidoamine dendrimers on 3-aminopropyl functionalized silica-coated magnetite nanoparticles, and used for rapid removal of lead (II) from aqueous medium. After each adsorption process, the supernatant was successfully acquired from reaction mixture by the magnetic separation, and then analyzed by employing ICP-OES. Chemical and physical characterizations of new nanomaterials were confirmed by XRD, FT-IR, SEM, TEM, and VSM. Maximum adsorption capacities (qm) of both prepared new nanostructured adsorbents were compared with each other and also with some other adsorbents. The kinetic data were appraised by using pseudo-first-order and pseudo-second-order kinetic models. Adsorption isotherms were found to be suitable with both Langmuir and Freundlich isotherm linear equations. The maximum adsorption capacities for MNPs-G1-Mu and MNPs-G2-Mu were calculated as 208.33 mg g-1 and 232.56 mg g-1, respectively. Antimicrobial activities of nanoparticles were also examined against various microorganisms by using microdilution method. It was determined that MNPs-G1-Mu, MNPs-G2-Mu and lead (II) adsorbed MNPs-G2-Mu showed good antimicrobial activity against S. aureus ATTC 29213 and C. Parapsilosis ATTC 22019. MNPs-G1-Mu also showed antimicrobial activity against C. albicans ATTC 10231.

Proline-based organocatalyst-mediated asymmetric aldol reaction of acetone with substituted aromatic aldehydes: an experimental and theoretical study.

This work involves a facile synthesis of three (S) -proline-based organocatalysts with C2 symmetry and their effects in enantioselective aldol reaction of acetone with substituted aromatic aldehydes. Moderate enantioselectivities (up to 61% ee) were obtained depending on the nature of the substituents on the aryl ring. Computational calculations at HF/6-31 + G(d) level were employed to underline the enantioselectivity imposed by all the organocatalysts. Higher calculations at B3LYP/6-311 ++ G(d,p) scrf=(solvent=dichloromethane)//B3LYP/6-31 + G(d) levels of theory were also performed for the aldol reaction of acetone with benzaldehyde and 4-nitrobenzaldehyde catalyzed by 1. The computational outcomes were consistent with those produced by experimental results and they were valuable to elucidate the mechanism for the observed stereoselectivity.

Dual inhibitor design for HIV-1 reverse transcriptase and integrase enzymes: a molecular docking study.

HIV-1, a member of Retroviruses' Lentivirus family, is the causative agent of AIDS. The virus is common throughout the world and leaves the body vulnerable to infections by suppressing the human immune system. Reverse transcriptase and integrase are two of three HIV-1 essential enzymes which perform important virus life cycle functions. In recent years, researchers started to design new inhibitors which could inhibit multiple targets for treatment of AIDS. In respect to this, RT and IN are two enzymes suitable for the development of dual inhibitors. To realize this aim, here we have designed new inhibitors by using approved reverse transcriptase and integrase inhibitors as drug design templates. Totally 426 ligands, which are filtered from 858 ligands by druggability properties were docked to crystal structure of reverse transcriptase and since there was no full-length structure of HIV-1 IN, same ligands were docked to Prototype Foamy Virus integrase structure. From the docking results, B099 was determined to be the best binding ligand to RT enzyme with a binding free energy of -12.63 kcal/mole and B249 was the best ligand for IN enzyme with a score of -19.83 kcal/mole. These binding scores demonstrate that these ligands are more active than Raltegravir for integrase and Rilpivirine for reverse transcriptase which are also used for docking method validation. B205, B214, B233, B242, B246, B249, B253 and B254 are the some of ligands found to have good binding scores for both enzymes and could be considered as new inhibitor candidates as dual inhibitors.Communicated by Ramaswamy H. Sarma.

A facile synthesis of amide-based receptors under microwave conditions: investigation of their anion recognition properties by experimental and computational tools.

Two novel amide-based receptors were synthesized under microwave irradiation. Their chemical structures were confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. The binding properties of these amide-based receptors to various anions (H2PO4-, HSO4-, C6H5CO2-, CH3CO2-, ClO4-, F-, Cl-, and Br-) were examined by UV titration in THF at 20 °C. The results indicated that the receptors form 1:1 complexes with anions and they have the strongest affinity for fluoride (F-) among the anions considered. Molecular dynamics calculations by AMBER and quantum mechanical calculations performed at the B3LYP and M062X levels of theory using the 6-31 + g(d,p) basis set provided models for the complexation mode between the receptors and anions and yielded binding energies for the complexes. Graphical abstract The computed interaction mode of tripodals (1a and 1b) with fluoride.

The origin of exo-stereoselectivity of norbornene in hetero Diels-Alder reactions.

In this study the exo selectivity in the hetero Diels-Alder reaction of atropisomeric 5-benzylidine-2-arylimino-3-aryl-thiazolidine-4-thiones with norbornene was investigated with computational tools. Taking into account the M/P chiral character of the o-methoxyphenyl substituted heterodienes in addition to the exo/endo selectivity, 8 different transition structures were located. Based on the direction of approach of the diene and the dienophile for each plausible path it is found that endo products are not preferred because of the large distortion of norbornene and the rather eclipsed conformations of these transition state structures. Computational results are consistent with the experimental exo/endo selectivity. The computational methodology (M06-2X/6-31+G(d)//B3LYP/6-31+G(d)) was justified by comparison of the experimental rotational barriers with the calculated ones for selected compounds.

Experimental and theoretical study of the mechanism of hydrolysis of substituted phenyl hexanoates catalysed by globin in the presence of surfactant.

The bimolecular rate constants for the globin- and alkali-catalysed hydrolysis of substituted phenyl hexanoates in the absence and presence of cetyltrimethylammonium bromide (CTAB) obey Brønsted equations with ß(lg) = -0.53 (globin-catalysed), -0.68 (globin-catalysed in CTAB), -0.34 (in water) and -0.74 (in CTAB), respectively. The slopes indicate that the microsolvation environments associated with the transition states of the catalysed reactions are different from those that occur in aqueous medium. The slope (-0.74) for the reaction in CTAB implies that it proceeds in a less polar medium. The larger ß(lg) value (-0.53) obtained for the globin-catalysed reaction compared to that for the uncatalysed one may be attributed to either the less polar microenvironments of the transition states or the involvement of one of the imidazole groups as a nucleophile. The results from a study of the effect of pH on the reactivity provide evidence for the latter assumption. All of the ligands were docked into the hydrophobic pocket of the protein, and the resulting docking scores ranged from -30.76 to -23.61 kcal mol⁻¹. Molecular dynamic simulations and MM-PBSA/GBSA calculations performed for the complexes gave insight into the binding modes of globin to the esters, which are consistent with experimental results. The calculations yielded comparable free energies of binding to the experimental ones for 4-nitrophenyl and 4-chloro-2-nitrophenyl hexanoates. In conclusion, information obtained from the linear free-energy relationship is still very useful for elucidating the mechanisms of organic reactions, including enzyme-catalysed reactions. This approach is further supported by the utilization of computational tools.

Computational design of a full-length model of HIV-1 integrase: modeling of new inhibitors and comparison of their calculated binding energies with those previously studied.

A full-length model of integrase (IN) of the human immunodeficiency virus type 1 (HIV-1) was constructed based on the distinctly resolved X-ray crystal structures of its three domains, named N-terminal, catalytic core and C-terminal. Thirty-one already known inhibitors with varieties of structural differences as well as nine newly tested ones were docked into the catalytic core. The molecular dynamic (MD) and binding properties of these complexes were obtained by MD calculations. The binding energies calculated by molecular mechanic/Poisson Boltzmann solvation area were significantly correlationed with available IC50. Four inhibitors including two newly designed were also docked into the full-length model and their MD behaviors and binding properties were calculated. It was found that one of the newly designed compounds forms a better complex with HIV-1 IN compared to the rest including raltegravir. MD calculations were performed with AMBER suite of programs using ff99SB force field for the proteins and the general Amber force field for the ligands. In conclusion, the results have produced a promising standpoint not only in the construction of the full-length model but also in development of new drugs against it. However, the role of multimer formation and the involvement of DNAs, and their subsequent effect on the complexation and inhibition, are required to arrive at a conclusive decision.