In silico profiling of histone deacetylase inhibitory activity of compounds isolated from Cajanus cajan

Background Cancer is responsible for high morbidity and mortality globally. Because the overexpression of histone deacetylases (HDACs) is one of the molecular mechanisms associated with the development and progression of some diseases such as cancer, studies are now considering inhibition of HDAC as a strategy for the treatment of cancer. In this study, a receptor-based in silico screening was exploited to identify potential HDAC inhibitors among the compounds isolated from Cajanus cajan, since reports have earlier confirmed the antiproliferative properties of compounds isolated from this plant. Results Cajanus cajan-derived phytochemicals were docked with selected HDACs, with givinostat as the reference HDAC inhibitor, using AutodockVina and Discovery Studio Visualizer, BIOVIA, 2020. Furthermore, absorption, distribution, metabolism and excretion (ADME) drug-likeness analysis was done using the Swiss online ADME web tool. From the results obtained, 4 compounds; betulinic acid, genistin, orientin and vitexin, were identified as potential inhibitors of the selected HDACs, while only 3 compounds (betulinic acid, genistin and vitexin) passed the filter of drug-likeness. The molecular dynamic result revealed the best level of flexibility on HDAC1 and HDAC3 compared to the wild-type HDACs and moderate flexibility of HDAC7 and HDAC8. Conclusions The results of molecular docking, pharmacokinetics and molecular dynamics revealed that betulinic acid might be a suitable HDAC inhibitor worthy of further investigation in order to be used for regulating conditions associated with overexpression of HDACs. This knowledge can be used to guide experimental investigation on Cajanus cajan-derived compounds as potential HDAC inhibitors.

Chemical, Pharmacological and Computerized Molecular Analysis of Stem’s Extracts of Bauhinia scandens L. Provide Insights into the Management of Diarrheal and Microbial Infections

Bauhinia scandens L. (Family: Fabaceae) is commonly used to treat cholera, diarrhea, asthma, and diabetes disorder in integrative medicine. This study aimed to screen the presence of phytochemicals (preliminary and UPLC-QTOF–M.S. analysis) and to examine the pharmacological activities of Bauhinia scandens L. stems (MEBS) stem extracts. Besides, in silico study was also implemented to elucidate the binding affinity and drug capability of the selected phytochemicals. In vivo anti diarrheal activity was investigated in mice models. In vitro, antibacterial and antifungal properties of MEBS against several pathogenic strains were evaluated using the disc diffusion method. In addition, in silico study has been employed using Discovery studio 2020, UCFS Chimera, PyRx autodock vina, and online tools. In the anti-diarrheal investigation, MEBS showed a significant dose-dependent inhibition rate in all three methods. The antibacterial and antifungal screening showed a remarkable zone of inhibition, of the diameter 14–26 mm and 12–28 mm, by MEBS. The present study revealed that MEBS has remarkable anti-diarrheal potential and is highly effective in wide-spectrum bacterial and fungal strains. Moreover, the in silico study validated the results of biological screenings. To conclude, MEBS is presumed to be a good source in treating diarrhea, bacterial and fungal infections.

The design of bioactive marine peptides as a HIV-1 protease inhibitor

Background: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV or AIDS) is a disease related to the human immune system. Given its important role in viral replication, HIV1 protease (HIV1 PR) becomes the major therapeutic target in the treatment of AIDS. In this case, we need a dynamic aspect of molecular interactions that can demonstrate the important role of conformational variability in the design of HIV1 PR inhibitors. There are several inhibitor candidates from marine organisms, such as the LLEYSL and LLEYSI bioactive peptides produced by oysters (Crassostrea gigas). Objective: Proteinpeptide docking method was used in silico to identify, evaluate, and explore the molecular interactions between bioactive peptide molecules and HIV-1 protease macromolecules. Methods: The sequencing of bioactive peptide molecules was modeled into 3D conformation using the PEPFOLD software. The best conformation was chosen for the study of molecular interactions against HIV1 protease macromolecules using the PatchDock software. The molecular interactions formed were further observed using the BIOVIA Discovery Studio 2020 software. Results: The results of this study indicated that the LLEYSL bioactive peptide had the best affinity with an ACE score of minus 1284.70 kJ per mol. Conclusion: Bioactive peptide molecule is predicted to be a candidate for HIV1 protease inhibitor. Keywords: AIDS, HIV1 protease, bioactive peptides, protein-peptide docking, in silico

Molecular Docking of the Terpenes in Gorgonian Corals to COX-2 and iNOS Enzymes as Anti-Inflammatory

Background: The inflammatory pathway is induced by cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) enzymes, so it requires the development of its inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs), but they have side effects. Therefore, the discovery and development of natural medicine as a lead compound are needed. The gorgonian corals have been reported to contain cyclic diterpenes with anti-inflammatory activities. The specific anti-inflammatory inhibitor potential has not been reported regarding these secondary metabolites, whether in COX-2 or iNOS. Thus, the in silico method is the right alternative. Objective: This study aimed to determine the potency of fifteen terpenes of the various gorgonian corals to COX-2 and iNOS enzymes as an anti-inflammatory Methods: Molecular docking was performed using ChemDraw Ultra 12.0, Chem3D Pro 12.0, Biovia Discovery Studio 2016 Client®, Autodock Tools 4.2, prediction pharmacokinetics (Pre-ADMET), and oral administration (Lipinski rule of five). Results: Potential terpenes based on ΔG (kcal/mol) and Ki (nM) to COX-2 were gyrosanol B (-10,32; 27,15), gyrosanol A (-10,20; 33,57), echinolabdane A (-9,81; 64,76). Only nine terpenes were specific to COX-2 active sites, while for iNOS were palmonine F (-7.76; 2070), briarenol C (-7.55; 2910), and all test compounds binding to the iNOS active sites. Pre-ADMET prediction obtained that HIA was very excellent (70–100%), Caco-2 had moderate permeability (4–70 nm sec-1), and PPB had strong binding (> 90%). Eight terpenes qualified for the Lipinski rule of five. Conclusion: NOS was a specific target for terpenes based on the free energy of binding (ΔG).

Virtual prediction of purple rice ferulic acid as anti-inflammatory of TNF-α signaling

Purple rice is one of the main sources of ferulic acid (FA). Some studies reported anti-inflammatory properties of FA, but the interaction of FA with TNF-α signaling has not been elucidated. TNF-α is a target for anti-inflammatory drug research due to its major role in the inflammatory process. This study aims to investigate the interaction of FA with TNF-α and TNF-α receptor (TNFR) through in silico study and evaluate the drug-like properties and biological activity of FA. The interactions among FA (CID 445858), TNF-α (2AZ5), and TNFR (1NCF) were docked by Hex 8.0.0 Cuda, then visualized by Discovery Studio 2020 and LigPlot V.1.4.5. Apigenin-7-glucuronide (AG, CID 5319484) was used as the positive control. The drug-like properties were predicted by Lipinski’s rule of five and the biological activity was analyzed by PASS online. FA showed good properties as a drug-like molecule and biological activity as an anti-inflammatory. FA also showed good interaction with TNF-α and TNFR. FA bound to TNF-α at Asn92(B), Val91(B), Leu93(B), Phe124(B), Phe124(D), and Leu93(D) residues with docking energy of -214.6 kJ/mol, and bound to TNFR at Pro16(A), Glu56(B), Cys55(B), Glu54(B) residues with docking energy of -191.1 kJ/mol. FA could inhibit TNF-α – TNFR interaction by binding to TNFR at Glu54 residue, the same inhibition mechanism to AG which bind to TNFR at Glu54 and Val90. The current study shows that FA has the potential as an anti-inflammatory of TNF-α signaling and can be developed as an oral anti-inflammatory drug candidate.

ANÁLISE COMPUTACIONAL DA INTERAÇÃO ENTRE O CANAL IÔNICO DE α-HL E COMPOSTOS TIAZOLIDÍNICOS

Introdução: Staphylococcus aureus (S. aureus) é uma bactéria associada a diversas infecções, tanto na comunidade quanto em ambiente hospitalar, ocasionando desde infecção cutânea até septicemia(1). Um importante fator de virulência é a exotoxina alfa-hemolisina (α-HL), que oligomeriza e forma canais iônicos transmembranares nas células-alvo, permitindo o fluxo livre de várias espécies químicas, resultando na morte celular(2). Diversas cepas de S. aureus exibem multirresistência aos antibióticos, limitando as opções de tratamento. Os derivados tiazolidínicos podem ser uma boa alternativa para bloquear a α-HL, pois possuem amplas propriedades bioativas, como por exemplo a antimicrobiana para cepas multirresistentes, sendo eficazes contra o S. aureus e inibindo o seu crescimento(3). Objetivos: Dada a importância da busca de compostos com ação antibacteriana, via bloqueio da α-HL, este trabalho visa analisar, via docagem molecular, a interação de derivados tiazolidínicos 5-benzilideno com o canal iônico formado pela toxina. Métodos: A estrutura cristalográfica da α-HL de S. aureus foi obtida pelo Protein Data Bank (PDB) e utilizou-se o MolView para modelagem dos compostos denominados GQ294 e GQ443, posteriormente submetidos ao Avogadro 1.1.1 para minimização de energia molecular. A docagem foi realizada pelo DockThor e os resultados foram analisados utilizando o Discovery Studio Visualizer. Resultados: A partir dos resultados de docagem pelo DockThor, foi obtida uma classificação dos compostos de acordo com suas energias totais e scores de afinidade com a toxina. Os valores de energia total do GQ443 e GQ294 foram iguais a -15,152 KJ/ mol e -19,009 KJ/ mol, respectivamente. Enquanto o score de afinidade de GQ443 e GQ294 foi de -6,820 Kcal/ mol e -5,902 Kcal/ mol respectivamente. As análises obtidas a partir do Discovery Studio Visualizer demonstraram que os dois compostos interagem com a região de constrição do canal iônico, principalmente com os resíduos GLU 111 e LYS 147, sendo estas interações mediadas principalmente por ligações de hidrogênio, além de interações do tipo cátionpi, pi-alquila, pi-enxofre. Esses dados corroboram com outros trabalhos já encontrados na literatura(4). Conclusões: Os resultados indicam, preditivamente, que os compostos GQ443 e GQ294 interagem com o canal da α-HL na região de constrição, sugerindo um bloqueio de sua atividade. São necessários dados experimentais para elucidar os dados teóricos já obtidos.

Novel inhibitors designing against the potential drug target of Plasmodium falciparum M17 Leucyl Aminopeptidase - PfM17LAP

Malaria is one of the major disease of concern worldwide especially in the African regions. According to the recent WHO reports, African regions share 95% of the total deaths worldwide that occurs due to malaria. Plasmodium falciparum M17 Leucyl Aminopeptidase (PfM17LAP) plays an important role in the regulation of amino acids release and for the survival of the parasite. We performed molecular docking and simulation studies to find the potential inhibitors against PfM17LAP using ChEMBL antimalarial library. Molecular docking studies and post-docking analysis revealed that molecules CHEMBL369831 and CHEMBL176888 showed better binding than the reference molecule BESTATIN. LibDock and X-SCORES of molecules BES, CHEMBL369831 and CHEMBL176888 are 130.071, 230.38, 223.56 and -8.75 Kcal/mol, -10.90 Kcal/mol, -11.05 Kcal/mol respectively. ADMET profiling of the top ten ranked molecules was done by using the Discovery Studio. Molecular dynamic studies revealed that the complex PfM17LAP-CHEMBL369831 is stable throughout the simulation. Finally, we have reported novel inhibitors which possess more binding affinity towards PfM17LAP. Key words: Malaria, M17 Leucyl Aminopeptidase, ADMET, X-SCORE

In Silico Approaches to Identify Polyphenol Compounds as α-Glucosidase and α-Amylase Inhibitors against Type-II Diabetes

Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both α-glucosidase and α-amylase enzymes inhibitors can suppress peaks of postprandial glucose with surplus adverse effects, leading to efforts devoted to urgently seeking new anti-diabetes drugs from natural sources for delayed starch digestion. This review attempts to explore 10 families e.g., Bignoniaceae, Ericaceae, Dryopteridaceae, Campanulaceae, Geraniaceae, Euphorbiaceae, Rubiaceae, Acanthaceae, Rutaceae, and Moraceae as medicinal plants, and folk and herb medicines for lowering blood glucose level, or alternative anti-diabetic natural products. Many natural products have been studied in silico, in vitro, and in vivo assays to restrain hyperglycemia. In addition, natural products, and particularly polyphenols, possess diverse structures for exploring them as inhibitors of α-glucosidase and α-amylase. Interestingly, an in silico discovery approach using natural compounds via virtual screening could directly target α-glucosidase and α-amylase enzymes through Monte Carto molecular modeling. Autodock, MOE-Dock, Biovia Discovery Studio, PyMOL, and Accelrys have been used to discover new candidates as inhibitors or activators. While docking score, binding energy (Kcal/mol), the number of hydrogen bonds, or interactions with critical amino acid residues have been taken into concerning the reliability of software for validation of enzymatic analysis, in vitro cell assay and in vivo animal tests are required to obtain leads, hits, and candidates in drug discovery and development.

MOLECULAR DOCKING STUDY OF NATURALLY OCCURRING COMPOUNDS AS INHIBITORS OF COVID -19

Objectives: The worldwide spread of COVID-19 is an emergent issue to be tackled. Currently, several works in various field have been made in rather short period. The present study aimed to assess bioactive compounds found in medicinal plants as potential COVID-19 Mpro inhibitors using molecular docking study. Methods: The docking analyses were performed by using Autodock, Discovery Studio Visualiser and Igemdock. Results: The binding energy obtained from the docking of 6LU7 with native ligand cupressuflavone is -8.9 kcal/mol. Conclusion: These findings will provide the opportunities to identify the right drug to combat COVID-19.

Molecular Docking Studies on Phenolic Constituents of Anethum graveolens L. Seed Extracts

Background: There are studies indicating that aqueous or hydroalcoholic dill extracts showed higher antioxidant activity compared to other fractions. Molecular docking studies would be relevant to get information on the mechanism of action of the phenolic constituents of Anethum graveolens seed extracts as bioactive compounds. Methodology: In order to perform the docking studies of antioxidant activity of phenolic constituents of Anethum graveolens seed extracts, BIOVIA Discovery Studio and AutoDock Vina software were used. Results: The orientation of flavonoids within Hck and CYP2C9 binding sites has been shown to be the main reason for their inhibitory potency. Conclusion: Molecular docking studies indicate that the compounds identified interact with the target enzymes Hck and CYP2C9 at molecular level through their condensed ring systems and hydroxyl substituents and therefore support the antioxidant capacity of the studied phenolic compounds.