DPP-IV Inhibitory Phenanthridines: Ligand, Structure-Based Design and Synthesis

2020 ◽  
Vol 16 (3) ◽  
pp. 295-307
Author(s):  
Reema A. Khalaf ◽  
Dalal Masalha ◽  
Dima Sabbah
Keyword(s):  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Ligand Docking ◽  
Health Concern ◽  
Aromatic Rings ◽  
Oral Antidiabetic Agents ◽  
Design And Synthesis ◽  
Dpp Iv ◽  
Novel Scaffold

Background: Lately, diabetes has become the main health concern for millions of people around the world. Dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged as a new class of oral antidiabetic agents. Formerly, acridines, N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives, and sulfamoyl-phenyl acid esters were designed and developed as new DPP-IV inhibitors. Objective: This study aims to develop a pharmacophore model of DPP-IV inhibitors and to evaluate phenanthridines as a novel scaffold for inhibiting DPP-IV enzyme. In addition, to assess their binding interactions with the enzyme through docking in the binding site of 4A5S (PDB). Methods: Herein, Quantum–Polarized Ligand Docking (QPLD) and ligand-based pharmacophore modeling investigations were performed. Three novel 3,8-disubstituted-6-phenyl phenanthridine derivatives 3-5 have been designed, synthesized and characterized. In vitro biological testing against DPP-IV was carried out using fluorometric assay kit. Results: QPLD study demonstrates that compounds 3-5 forms H-bond with Lys554, Trp629, and Tyr631, besides charge transfer interaction between their aromatic rings and the aromatic rings of Tyr547 and Tyr666. Moreover, they fit the three pharmacophoric point features of DPP-IV inhibitors and were proven to have in vitro DPP-IV inhibitory activity where compound 5 displayed a % inhibition of 45.4 at 100 μM concentration. Conclusion: Phenanthridines may serve as a potential lead compound for developing new DPP-IV inhibitors as a promising antidiabetic agent. Computational results suggest future structural simplification.

Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

2019 ◽  
Vol 16 (7) ◽  
pp. 775-784
Author(s):  
Richa Arya ◽  
Satya Prakash Gupta ◽  
Sarvesh Paliwal ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medical Condition ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Pyridine Derivative ◽  
Cleavage Enzyme ◽  
Bace 1

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation

2020 ◽  
Vol 16 ◽  
Author(s):  
Reema Abu Khalaf ◽  
Shorooq Alqazaqi ◽  
Maram Aburezeq ◽  
Dima Sabbah ◽  
Ghadeer Albadawi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Biological Evaluation ◽  
Ligand Docking ◽  
Biological Assessment ◽  
Hypoglycemic Agents ◽  
Binding Affinities ◽  
Oral Hypoglycemic Agents ◽  
Design Synthesis ◽  
Dpp Iv

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas. Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones. Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

scholarly journals Design, Synthesis and Biological Evaluation of N4-Sulfonamido-Succinamic, Phthalamic, Acrylic and Benzoyl Acetic Acid Derivatives as Potential DPP IV Inhibitors

2013 ◽  
Vol 7 (1) ◽  
pp. 39-48 ◽  
Author(s):  
Reema Abu Khalaf ◽  
Ghassan Abu Sheikha ◽  
Mahmoud Al-Sha'er ◽  
Mutasem Taha
Keyword(s):  
Acetic Acid ◽  
Type Ii Diabetes Mellitus ◽  
Biological Evaluation ◽  
Diabetic Patients ◽  
Type Ii ◽  
Design Synthesis ◽  
Multifunctional Protein ◽  
Design And Synthesis ◽  
Dpp Iv

As incidence rate of type II diabetes mellitus continues to rise, there is a growing need to identify novel therapeutic agents with improved efficacy and reduced side effects. Dipeptidyl peptidase IV (DPP IV) is a multifunctional protein involved in many physiological processes. It deactivates the natural hypoglycemic incretin hormone effect. Inhibition of this enzyme increases endogenous incretin level, incretin activity and should restore glucose homeostasis in type II diabetic patients making it an attractive target for the development of new antidiabetic drugs. One of the interesting reported anti- DPP IV hits is Gemifloxacin which is used as a lead compound for the development of new DPP IV inhibitors. In the current work, design and synthesis of a series of N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives was carried out. The synthesized compounds were evaluated for their in vitro anti-DPP IV activity. Some of them have shown reasonable bioactivity, where the most active one 17 was found to have an IC50 of 33.5 μM.

scholarly journals STRUCTURE-ACTIVITY RELATIONSHIP: STUDY OF LEI-401 AS INHIBITOR OF NAPE-PLD BY PHARMACOPHORE MODEL

2021 ◽  
Vol 9 (5) ◽  
pp. 662-666
Author(s):  
Nilesh S. Kadu ◽  
Keyword(s):  
Metabolic Syndrome ◽  
Biological Activity ◽  
Phospholipase D ◽  
Pharmacophore Model ◽  
Structural Features ◽  
Pharmacophore Modeling ◽  
Physiological Processes ◽  
Structure Activity ◽  
Relationship Study

N-acyl-phosphatidylethanolamine phospholipase D (NAPE–PLD) is considered to be the principal enzyme that produces N-acylethanolamines (NAEs), a family of signaling lipids. NAEs are involved in numerous physiological processes such as appetite, satiety, pain, inflammation, fertility, stress, and anxiety. Furthermore, aberrant NAE levels are associated with metabolic syndrome and non-alcoholic steatohepatitis (NASH). Several inhibitors for NAPE–PLD have been reported. But most of the inhibitors showed poor to moderate potency for NAPE–PLD in vitro. Recently, Mario van der Stelt et al describe the SAR of NAPE–PLD inhibitors that afforded LEI–401 in vitro. However, no attempt was instigated to produce a consensus pharmacophore model of LEI–401 as inhibitors of NAPE–PLD. Pharmacophore modeling is an efficient and useful approach to identify important patterns in a series of molecules for optimizations. The consensus pharmacophore model revealed the importance of structural features and their correlation with the biological activity.

Discovery of Potent Natural-Product-Derived SIRT2 Inhibitors Using Structure-Based Exploration of SIRT2 Pharmacophoric Space Coupled With QSAR Analyses

2021 ◽  
Vol 21 ◽  
Author(s):  
Mohammad A. Khanfar ◽  
Saja Alqtaishat
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Characteristic Curve ◽  
Pharmacophore Model ◽  
Qsar Model ◽  
Pharmacophore Modeling ◽  
Class Iii ◽  
Qsar Analysis ◽  
Starting Point

Background: SIRT2 belongs to a class III of histone deacetylase (HDAC) and has crucial roles in neurodegeneration and malignancy. Objective: Discover structurally novel natural-product-derived SIRT2 inhibitors. Methods: Structure-based pharmacophore modeling integrated with validated QSAR analysis were implemented to discover structurally novel SIRT2 inhibitors from natural products database. The targeted QSAR model combined molecular descriptors with structure-based pharmacophore capable of explaining bioactivity variation of structurally diverse SIRT2 inhibitors. Manually built pharmacophore model, validated with receiver operating characteristic curve, and selected using the statistically optimum QSAR equation, was applied as a 3D-search query to mine AnalytiCon Discovery database of natural products. Results : Experimental in vitro testing of highest-ranked hits identified asperphenamate and salvianolic acid B as active SIRT2 inhibitors with IC50 values in low micromolar range. Conclusion: New chemical scaffolds of SIRT2 inhibitors have been identified that could serve as a starting point for lead-structure optimization.

scholarly journals Using bioinformatics tools for the discovery of Dengue RNA-dependent RNA polymerase inhibitors

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5068 ◽  
Author(s):  
Nomagugu B. Nncube ◽  
Pritika Ramharack ◽  
Mahmoud E.S. Soliman
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Active Site ◽  
Mammalian Cells ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Health Concern ◽  
Innovative Drug ◽  
Rna Dependent Rna Polymerase ◽  
Bioinformatics Tools

BackgroundDengue fever has rapidly manifested into a serious global health concern. The emergence of various viral serotypes has prompted the urgent need for innovative drug design techniques. Of the viral non-structural enzymes, the NS5 RNA-dependent RNA polymerase has been established as a promising target due to its lack of an enzymatic counterpart in mammalian cells and its conserved structure amongst all serotypes. The onus is now on scientists to probe further into understanding this enzyme and its mechanism of action. The field of bioinformatics has evolved greatly over recent decades, with updated drug design tools now being publically available.MethodsIn this study, bioinformatics tools were used to provide a comprehensive sequence and structural analysis of the two most prominent serotypes of Dengue RNA-dependent RNA polymerase. A list of popularflavivirusinhibitors were also chosen to dock to the active site of the enzyme. The best docked compound was then used as a template to generate a pharmacophore model that may assist in the design of target-specific Dengue virus inhibitors.ResultsComparative sequence alignment exhibited similarity between all three domains of serotype 2 and 3.Sequence analysis revealed highly conserved regions at residues Meth530, Thr543 Asp597, Glu616, Arg659 and Pro671. Mapping of the active site demonstrated two highly conserved residues: Ser710 and Arg729. Of the active site interacting residues, Ser796 was common amongst all ten docked compounds, indicating its importance in the drug design process. Of the ten dockedflavivirusinhibitors, NITD-203 showed the best binding affinity to the active site. Further pharmacophore modeling of NITD-203 depicted significant pharmacophoric elements that are necessary for stable binding to the active site.DiscussionThis study utilized publically available bioinformatics tools to provide a comprehensive framework on Dengue RNA-dependent RNA polymerase. Based on docking studies, a pharmacophore model was also designed to unveil the crucial pharmacophoric elements that are required when constructing an efficacious DENV inhibitor. We believe that this study will be a cornerstone in paving the road toward the design of target-specific inhibitors against DENV RdRp.

scholarly journals Identification of Human Leukotriene A4 Hydrolase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2871
Author(s):  
Suaad A. Audat ◽  
Nizar A. Al-Shar’i ◽  
Buthina A. Al-Oudat ◽  
Amanda Bryant-Friedrich ◽  
Mel F. Bedi ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
3D Structure ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Leukotriene B4 ◽  
Hydrolase Activity ◽  
Lipid Mediator ◽  
Leukotriene A4 Hydrolase ◽  
Leukotriene A4

Leukotriene B4 (LTB4) is a potent, proinflammatory lipid mediator implicated in the pathologies of an array of inflammatory diseases and cancer. The biosynthesis of LTB4 is regulated by the leukotriene A4 hydrolase (LTA4H). Compounds capable of limiting the formation of LTB4, through selective inhibition of LTA4H, are expected to provide potent anti-inflammatory and anti-cancer agents. The aim of the current study is to obtain potential LTA4H inhibitors using computer-aided drug design. A hybrid 3D structure-based pharmacophore model was generated based on the crystal structure of LTA4H in complex with bestatin. The generated pharmacophore was used in a virtual screen of the Maybridge database. The retrieved hits were extensively filtered, then docked into the active site of the enzyme. Finally, they were consensually scored to yield five hits as potential LTA4H inhibitors. Consequently, the selected hits were purchased and their biological activity assessed in vitro against the epoxide hydrolase activity of LTA4H. The results were very promising, with the most active compound showing 73.6% inhibition of the basal epoxide hydrolase activity of LTA4H. The results from this exploratory study provide valuable information for the design and development of more potent and selective inhibitors.

Synthesized Drug from Medicinal Plant phytochemicals Effectively Targets ECM1 Gene Mutations in Ulcerative Colitis

2021 ◽  
Vol 18 ◽  
Author(s):  
Anum Munir ◽  
Lianhai Hu
Keyword(s):  
Ulcerative Colitis ◽  
Tissue Damage ◽  
Matrix Protein ◽  
Gene Mutations ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Extracellular Matrix Protein ◽  
Nucleotide Polymorphisms ◽  
Qilu Hospital

: Ulcerative colitis (UC); an inflammatory bowel disease primarily affects the mucosa of the colon. Depending on its mode of appearance, it can affect either the entire colon or even the distal rectum. UC can manifest in both genders and every generation, but most generally appear in people between the ages of 15 and 30. The extracellular matrix protein-1 (ECM1) gene is an important candidate, mutations leading to tissue damage in patients with ECM1 single-nucleotide polymorphisms are likely to intensify tissue damage caused by Metalloproteinase9 resulting in UC. In this analysis, Approval for the synthesis of Chemical Compound was obtained from the scientific committee of theDepartment of Traditional Chinese Medicine, Qilu Hospital, China. Several derivatives used as UC therapy were selected to build the pharmacophore model, using a ligand-based pharmacophore modeling approach and virtual screenings were done for the identification of suitable drug compounds. The selected compound was then synthesized in-vitro and validated using the molecular docking technique. The synthesized compound fulfills all the characteristics of the non-toxic existence of other drug-likeness laws. The specific interactive amino acids found in the docked complex are arginine (ARG):47, lysine (LYS):54, phenylalanine (PHE):141, aspargine (ASN):51, serine (SER):219, histadine (HIS):144, PHE:214, valine (VAL):220, tyrosine (TYR):145, and TYR:284. The interaction of the synthesized compound with mutated TYR:284 of ECM1 confirmed the viability and safety of a drug molecule as a medication in Ulcerative Colitis care. In the future, its validity can be explored in the laboratory and this synthesized compound can be used as a medication target in clinical studies against TYR:284 mutation in the ECM1 gene Keywords: ECM1, Inflammation, Medicinal Plants, Tyrosine

Bioactivity of Phenolic Compounds Extracted from Strawberry against Formation of Pseudomonas aeruginosa Biofilm

2019 ◽  
Vol 10 (01) ◽  
Author(s):  
Baydaa Hussein ◽  
Zainab A. Aldhaher ◽  
Shahrazad Najem Abdu-Allah ◽  
Adel Hamdan
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Phenolic Compounds ◽  
Biofilm Formation ◽  
Opportunistic Infections ◽  
Formation Rate ◽  
Hydrocarbon Chain ◽  
Health Concern ◽  
Gas Chromatography Mass Spectrometry ◽  
Phenolic Contents

Background: Biofilm is a bacterial way of life prevalent in the world of microbes; in addition to that it is a source of alarm in the field of health concern. Pseudomonas aeruginosa is a pathogenic bacterium responsible for all opportunistic infections such as chronic and severe. Aim of this study: This paper aims to provide an overview of the promotion of isolates to produce a biofilm in vitro under special circumstances, to expose certain antibiotics to produce phenotypic evaluation of biofilm bacteria. Methods and Materials: Three diverse ways were used to inhibited biofilm formation of P.aeruginosa by effect of phenolic compounds extracts from strawberries. Isolates produced biofilm on agar MacConkey under certain circumstances. Results: The results showed that all isolates were resistant to antibiotics except sensitive to azithromycin (AZM, 15μg), and in this study was conducted on three ways to detect the biofilm produced, has been detected by the biofilm like Tissue culture plate (TCP), Tube method (TM), Congo Red Agar (CRA). These methods gave a clear result of these isolates under study. Active compounds were analyzed in both extracts by Gas Chromatography-mass Spectrometry which indicate High molecular weight compound with a long hydrocarbon chain. Conclusion: Phenolic compounds could behave as bioactive material and can be useful to be used in pharmaceutical synthesis. Phenolic contents which found in leaves and fruits extracts of strawberries shows antibacterial activity against all strains tested by the ability to reduce the production of biofilm formation rate.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

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