Computational analysis and in vitro investigation on Citrus flavonoids for inflammatory, diabetic and AGEs targets

Abstract Flavonoids are a diverse class of polyphenolic substances largely found in plants including citrus peels and are reported to posess a variety of biological activities. We investigated important flavonoids apigenin, hesperidin, narigin, quercetin and tangeritine against diabetes and associated conditions. In current project drug likeness, ADMET analysis, molecular docking and in vitro assays were performed. The apigenin, quercetin and tanagretin exhibited compliance with Lipinski's rule of five. The molecular docking analysis showed best fit in transcriptional regulator 3TOP and 1IK3 in all tested compounds. During antioxidant assays, all flavonoids presented excellent activities. In the α-glucosidase assay, quercetin showed highest inhibition (76% at final concentration of 52 µg/ml) followed by tangeritin (73% at final concentration of 52 µg/ml). In case of 15-Lox assay, highest inhibition was seen in case of quercetin (75%) followed by apigenin (53%). In the AGEs assay, the quercetin showed 47% inhbition of protein cross link formation preceeded by the tenegretin exhited 37% inhibition. It was therefore concluded that tested flavonoids have significant activities in both in silico and in vitro models that is mainly due to differences in structural features and polar surface area.

In-Silico Study Of Molecular Properties, Bioactivity And Toxicity Of 2-(Substituted Benzylidene)Succinic Acids And Some Selected Anti-Inflammatory Drugs

Succinic acid and its derivatives have many important uses, especially in pharmaceutical and polymer industry. The 2-(substituted benzylidene)succinic acids also known as substituted phenylitaconic acids are utilized in the synthesis of some lignans, lignanamides and renin inhibitors. In view of this, the present in-silico study aimed to calculate the molecular properties, bioactivity score and toxicity of several benzylidenesuccinic acids as well as some selected anti-inflammatory drugs by computational methods. The study revealed that all the compounds obeyed Lipinski’s rule of five, indicating drug likeness properties. The bioactivity data revealed that the 2-(substituted benzylidene)succinic acids were active as Nuclear receptor ligands, Enzyme inhibitors, GPCR ligands and Ion channel modulators. Among all, 2-(3,5-di-tert-butyl-4-hydroxybenzylidene)succinic acid was predicted as non-toxic with better in-silico molecular properties and bioactivity as Nuclear receptor ligand, Enzyme inhibitor, GPCR ligand, Ion channel modulator and Protease inhibitor compared to some of the predicted anti-inflammatory drugs.

Identification of Gly/NMDA receptor Antagonist from Chromolaena odorata’s Derived compounds using Induced Fit Docking and ADME study

The ionotropic activation of N-methyl-D-aspartic acid (NMDA) plays asignificant role in different type of neurodegenerative disease, as it is a tetramer withtwo Glycine binding subunit and two glutamate subunits. NMDA receptor can beinhibited by either blocking of the glycine site or glutamate site. Previously reportedinhibitors of NMDA receptor focus on the inhibition of the glutamate subunit, which wasreported to be associated with side effects such as ataxia, memory deficits, andneurotoxicity. Therefore, different compounds with antagonistic effect are beenexplored on Gly/NMDA site. Glide XP docking was employed in screening phytoconstituent of Chromolaena odorata against Gly/NMDA receptor for hit compounds withantagonistic properties. The hit compounds were further subjected to Induced fitdocking (IFD) and Lipinski rule of five. The final selection was based on Rigid XP dockingscore using co-crystallized ligand as threshold docking score, interaction with receptorsite residues, and IFD score. Ferulic acid, caffeic acid and scutellarein recorded bindingaffinity of -8.752Kcal/mol, 10.004 Kcal/mol and -9.096 Kcal/mol respectively, which ishigher than the binding affinity of co-crystallized ligand. Induced fit score obtained were-614.38, -614.03 and -616.31 for ferulic acid, caffeic acid and scutellarein respectively.The result obtained in this study shows the potency of phytochemical from C. odorata toinhibit NMDA receptor. ADME study showed that the drug-like nature of thesecompounds.

Synthesis and in vitro Evaluation of Antifungal Properties of Some 4-Aryl-3-Methyl-1,2,3,4-Tetrahydroquinolines Derivatives / Síntesis y evaluación in vitro de las propiedades antifungicas de algunos derivados de 4-aril-3-metil-1,2,3,4-tetrahidroquinolinas / Síntese e avaliação in vitro das propriedades antifungicas de alguns derivados de 4-Aryl-3-Methyl-1,2,3,4-Tetrahydroquinolines

Two series of 4-aryl-3-methyl-1,2,3,4-tetrahydroquinoline derivatives were efficiently synthesized according to a two-step synthesis and evaluated as potential antifungal agents. The key step was the formation of the corresponding N-benzyltetrahydroquinolines 5 via a three-component cationic imino Diels-Alder cycloaddition. The second step was a catalytic debenzylation to obtain the N-unprotected tetrahydroquinolines 6. The products were isolated and purified by column chromatography. Substances were characterized using nuclear magnetic resonance (NMR) mass spectrometry (MS) and infrared spectroscopy (IR). All compounds were tested in vitro against standardized, clinically important fungi, including yeasts, hialohyphomycetes, and dermatophytes. These studies showed that between the tetrahydroquinoline series tested, compounds 6f and 6g showed antifungal activity, specifically against dermatophytes. The compound 6-methoxy-4-(4-hydroxi-3-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydroquinoline 6g exhibited the best in vitro activity (MIC 32-65 μg/mL). The results indicated that the elimination of benzyl group from the N-benzyltetrahydroquinolines derivatives, as well as the introduction of a hydroxyl group in the 4-aryl substituent caused a significant improvement in the antifungal activity. These results were supplemented by the in silico prediction; most of the tetrahydroquinolines evaluated showed high bioavailability, high drugs score and low potential risk.

Dos series de 4-aril-3-metil-1,2,3,4-tetrahidroquinolinas fueron sintetizadas de acuerdo con una metodología sintética de dos pasos y evaluadas como potenciales agentes antifúngicos. El paso clave involucró la formación de las correspondientes N-bencil tetrahidroquinolinas 5 vía una cicloadición imino Diels-Alder catiónica. El segundo paso consistió en obtener las tetrahidroquinolinas N-desprotegidas 6 vía una desbencilación catalítica. Los productos fueron aislados y purificados usando cromatografía en columna (CC). Las sustancias fueron identificadas usando resonancia magnética nuclear (RMN), espectrometría de masas (EM) y espectroscopia infrarroja (IR). Los compuestos fueron evaluados in vitro frente a cepas estandarizadas de hongos clínicamente relevantes, incluyendo levaduras, hialohifomicetes y dermatofitos. Estos estudios mostraron que, de las tetrahidroquinolinas ensayadas, los compuestos 6f y 6g mostraron actividad antifúngica, específicamente frente a dermatofitos. El compuesto 6-metoxi-4-(4-hidroxi-3-metoxifenil)-3-metil-1,2,3,4-tetrahidroquinolina 6g exhibió la mejor actividad (MIC 32-65 μg/mL). Los resultados indican que remover el grupo bencilo e introducir un grupo hidroxilo en el sustituyente arilo de las N-bencil tetrahidroquinolinas produce un mejoramiento de la actividad antifúngica. Predicciones in silico complementaron los resultados: la mayoría de las tetrahidroquinolinas ensayadas mostraron alta biodisponibilidad, altos "drug scores" y bajo riesgo potencial.

Duas séries de 4-aril-3-metil-1,2,3,4-tetrahidroquinolina foram sintetizadas de acordo com um método de síntese em duas etapas e avaliadas como potenciais agentes antifúngicos. O passo chave envolveu a formação dos correspondentes N-bencil tetrahidroquinolinas 5 via uma cicloadição de imino Diels-Alder catiónica. O segundo passo foi obter as N-tetrahidroquinolinas 6 através de uma desbenzilação catalítica. Os produtos foram purificados utilizando cromatografia em coluna. As substancias foram identificadas por ressonancia magnética nuclear (RMN), espectrometria de massa (EM) e espectroscopia de infravermelho (IR). Todos o compostos foram testados in vitro contra as estirpes padrao e os fungos clinicamente importantes, incluindo as leveduras, hialohifomicetes e dermatófitos. Estes estudos mostraram que entre a série de tetrahidroquinolinas (THQ) os compostos 6f e 6g mostraram atividade antifúngica, particularmente contra dermatófitos. O composto 6-metoxi-4-(4-hidroxi-3-metoxifenil)-3-metil-1,2,3,4-tetrahidroquinila 6g mostrou melhor atividade (MIC 32-65 μg/mL). Os resultados indicam que a remoção do grupo benzilo e a introdujo de um grupo hidroxilo no substituinte arilo do N-benzil-tetrahidroquinolina, resultou num aumento significativo da atividade antifúngica. Os resultados foram suplementados por previsöes in silico, que mostraram alta biodisponibilidade e pouco risco potencial da maioria dos tetrahidroquinolinas avaliados.

Virtual Screening of Molecular Properties and Bioactivity Score of Boswellic Acid Derivatives in Search of Potent Anti-Inflammatory Lead Molecule.

The aim of this study was to examine correlation between anti-inflammatory activity and molecular properties of the Boswellic acid derivatives in search of a lead compound through molinspiration cheminformatics software. Twelve naturally occurring and semisynthetic derivatives of Boswellic acid were selected for bioactivity prediction and drug likeness score on the basis of Lipinski’s rule. Aceclofenac and Hydrocortisone (cortisol) were used as reference standard for comparing the molecular properties and bioactivity score. None of the compounds fulfilled Lipinski’s rule as their Milog P score was above 5 suggesting these compounds are highly lipophilic with very poor aqueous solubility. All the screened compounds had minimum one and maximum three violations of Lipinski rule. BA and its derivatives showed good bioactivity score for drug targets including nuclear receptor ligand, protease inhibitor and enzyme inhibition and thus expected to have excellent pharmacological activity in vivo. The results of this study justify their topical application in arthritic conditions but some structural modifications in order to make the compound more polar will definitely improve oral bioavailability and thus the usefulness and therapeutic efficacy of BAs. Among all the boswellic acid derivatives, only compound number 2 is predicted to be orally active and is considered as a potential candidate for the further research as its bioactivity score due to high affinity for various drug targets was better than the standard (Cortisol and Aceclofenac) as well as among other tested compounds.

Lead finding from whole plant of Marrubium vulgare L. with Hepatoprotective Potentials through in silico methods

Objective: In the present study an attempt has been made to study the antihepatotoxic activity of active compounds in this plant through in silico methods. Methods: We have taken 12 compounds form this plant. All the compounds were further subjected to molecular propertied prediction and drug likeness by Molinspiration and found in compliance with Lipinski’s rule of five. Biochemical parameters like SGOT and SGPT were determined by Reitman and Frankel, ALP by Kind and King, TP by reported methods of Wooton. Results: All the compounds were showed expected similar bioactivity especially in case of enzyme inhibition. Compound Vulgarin showed no violation with good drug likeness score and biological activity as compare to standard drug Silibinin. Vulgarin exhibited a significant antihepatotoxic activity by reducing the elevated levels of serum enzymes such as serum glutamate oxaloacetate transaminase (SGOT) serum glutamate pyruvate oxaloacetate transaminase (SGPT) and alkaline phosphatase (ALP) while the total protein (TP) levels were increased when compared with standard drug silymarin against CCl4-induced toxicity in Wistar rats. These biochemical observations were also supplemented by histopathological examinations of the liver sections. Conclusions: We found that Vulgarin one of the twelve compounds is showed better drug likeness and biological activity against Silibinin. So this particular compound can be taken as lead compound for further drug discovery for hepatotoxic activity.

Lead finding from Phyllanthus debelis with hepatoprotective potentials

Objective: Present communication deals with the study of antihepatotoxic activity and molecular prediction of compounds isolated from Phyllanthus debelis in order to search lead compound. Methods: Five compounds from the whole plant of P. debelis were subjected to molecular properties prediction and drug-likeness by Lipinski rule of five & Molinspiration software. Results: All the compounds were found in compliance with Lipinski ‘Rule of Five’ except the Milog P valve of compound No. I-IV were found above five means these compounds have less permeability across the cell membrane. The Milog P valve of Compound No V & standard compound silibinin VI were found below five, suggest that the molecules have good permeability across the cell membrane. In respect of TPSA, all the compounds were within the limit i.e. 160 ?. The bioactivity score was also calculated for GPCR ligand, ion channel modulator, kinase inhibitor, nuclear receptor ligand. All the compound showed activity through enzyme inhibition.Conclusions:Our study shows that compound V debelolactone has good drug likeness score with no violations & good bioactivity score as compared to silibinin which is potent hepatoprotective drug. So compound V debelolactone can be a lead compound with hepatoprotective activity from Phyllanthus debelis.