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Pharmacophore Modelling and Virtual Screening Studies for the Discovery of Potential Natural Products Based PDE1B Inhibitor Lead Compounds

Shy TW, Gaurav A

Cent Nerv Syst Agents Med Chem, 2021;21(3):195-204.
PMID: 34970959 DOI: 10.2174/1871524922666211231115638

AIM: The aim of the present study was to apply pharmacophore based virtual screening to a natural product database to identify potential PDE1B inhibitor lead compounds for neurodegenerative and neuropsychiatric disorders.
BACKGROUND: Neurodegenerative and neuropsychiatric disorders are a major health burden globally. The existing therapies do not provide optimal relief and are associated with substantial adverse effects. This has resulted in a huge unmet medical need for newer and more effective therapies for these disorders. Phosphodiesterase (PDEs) enzymes have been identified as potential targets of drugs for neurodegenerative and neuropsychiatric disorders, and one of the subtypes, i.e., PDE1B, accounts for more than 90 % of total brain PDE activity associated with learning and memory process, making it an interesting drug target for the treatment of neurodegenerative disorders.
OBJECTIVES: The present study has been conducted to identify potential PDE1B inhibitor lead compounds from the natural product database.
METHODS: Ligand-based pharmacophore models were generated and validated; they were then employed for virtual screening of Universal Natural Products Database (UNPD) followed by docking with PDE1B to identify the best hit compound.
RESULTS: Virtual screening led to the identification of 85 compounds which were then docked into the active site of PDE1B. Out of the 85 compounds, six showed a higher affinity for PDE1B than the standard PDE1B inhibitors. The top scoring compound was identified as Cedreprenone.
CONCLUSION: Virtual screening of UNPD using Ligand based pharmacophore led to the identification of Cedreprenone, a potential new natural PDE1B inhibitor lead compound.
Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors

Gaurav A, Gautam V

Iran J Pharm Res, 2017;16(3):910-923.
PMID: 29201082

Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma and chronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known to reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. To achieve this goal, ligand based pharmacophore modeling approach is employed. Separate pharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGen algorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines, 2-arylpyrimidines, and triazines skeleton. Suitable training and test sets were created using the molecules as per the guidelines available for HypoGen program. Training set was used for hypothesis development while test set was used for validation purpose. Fisher validation was also used to test the significance of the developed hypothesis. The validated pharmacophore hypotheses for PDE4B and PDE4D inhibitors were used in sequential virtual screening of zinc database of drug like molecules to identify selective PDE4B inhibitors. The hits were screened for their estimated activity and fit value. The top hit was subjected to docking into the active sites of PDE4B and PDE4D to confirm its selectivity for PDE4B. The hits are proposed to be evaluated further using in-vitro assays.
Protein-Protein Interactions of Phosphodiesterases

Al-Nema MY, Gaurav A

Curr Top Med Chem, 2019;19(7):555-564.
PMID: 30931862 DOI: 10.2174/1568026619666190401113803

BACKGROUND: Phosphodiesterases (PDEs) are enzymes that play a key role in terminating cyclic nucleotides signalling by catalysing the hydrolysis of 3', 5'- cyclic adenosine monophosphate (cAMP) and/or 3', 5' cyclic guanosine monophosphate (cGMP), the second messengers within the cell that transport the signals produced by extracellular signalling molecules which are unable to get into the cells. However, PDEs are proteins which do not operate alone but in complexes that made up of a many proteins.
OBJECTIVE: This review highlights some of the general characteristics of PDEs and focuses mainly on the Protein-Protein Interactions (PPIs) of selected PDE enzymes. The objective is to review the role of PPIs in the specific mechanism for activation and thereby regulation of certain biological functions of PDEs.
METHODS: The article discusses some of the PPIs of selected PDEs as reported in recent scientific literature. These interactions are critical for understanding the biological role of the target PDE.
RESULTS: The PPIs have shown that each PDE has a specific mechanism for activation and thereby regulation a certain biological function.
CONCLUSION: Targeting of PDEs to specific regions of the cell is based on the interaction with other proteins where each PDE enzyme binds with specific protein(s) via PPIs.
Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia

Al-Nema MY, Gaurav A

Curr Top Med Chem, 2020;20(26):2404-2421.
PMID: 32533817 DOI: 10.2174/1568026620666200613202641

Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.
Fulltext In Silico Investigation of Flavonoids as Potential Trypanosomal Nucleoside Hydrolase Inhibitors

Ha CH, Fatima A, Gaurav A

Adv Bioinformatics, 2015;2015:826047.
PMID: 26640486 DOI: 10.1155/2015/826047

Human African Trypanosomiasis is endemic to 37 countries of sub-Saharan Africa. It is caused by two related species of Trypanosoma brucei. Current therapies suffer from resistance and public accessibility of expensive medicines. Finding safer and effective therapies of natural origin is being extensively explored worldwide. Pentamidine is the only available therapy for inhibiting the P2 adenosine transporter involved in the purine salvage pathway of the trypanosomatids. The objective of the present study is to use computational studies for the investigation of the probable trypanocidal mechanism of flavonoids. Docking experiments were carried out on eight flavonoids of varying level of hydroxylation, namely, flavone, 5-hydroxyflavone, 7-hydroxyflavone, chrysin, apigenin, kaempferol, fisetin, and quercetin. Using AutoDock 4.2, these compounds were tested for their affinity towards inosine-adenosine-guanosine nucleoside hydrolase and the inosine-guanosine nucleoside hydrolase, the major enzymes of the purine salvage pathway. Our results showed that all of the eight tested flavonoids showed high affinities for both hydrolases (lowest free binding energy ranging from -10.23 to -7.14 kcal/mol). These compounds, especially the hydroxylated derivatives, could be further studied as potential inhibitors of the nucleoside hydrolases.
Fulltext Docking based screening and molecular dynamics simulations to identify potential selective PDE4B inhibitor

Al-Nema M, Gaurav A, Lee VS

Heliyon, 2020 Sep;6(9):e04856.
PMID: 32984588 DOI: 10.1016/j.heliyon.2020.e04856

Inhibition of phosphodiesterase 4 (PDE4) is a promising therapeutic approach for the treatment of inflammatory pulmonary disorders, i.e. asthma and chronic obstructive pulmonary disease. However, the treatment with non-selective PDE4 inhibitors is associated with side effects such as nausea and vomiting. Among the subtypes of PDE4 inhibited by these inhibitors, PDE4B is expressed in immune, inflammatory and airway smooth muscle cells, whereas, PDE4D is expressed in the area postrema and nucleus of the solitary tract. Thus, PDE4D inhibition is responsible for the emetic response. In this regard, a selective PDE4B inhibitor is expected to be a potential drug candidate for the treatment of inflammatory pulmonary disorders. Therefore, a shared feature pharmacophore model was developed and used as a query for the virtual screening of Maybridge and SPECS databases. A number of filters were applied to ensure only compounds with drug-like properties were selected. Accordingly, nine compounds have been identified as final hits, where HTS04529 showed the highest affinity and selectivity for PDE4B over PDE4D in molecular docking. The docked complexes of HTS04529 with PDE4B and PDE4D were subjected to molecular dynamics simulations for 100ns to assess their binding stability. The results showed that HTS04529 was bound tightly to PDE4B and formed a more stable complex with it than with PDE4D.
Docking Studies of Curcumin and Analogues with Various Phosphodiesterase 4 Subtypes

Yi YX, Gaurav A, Akowuah GA

Curr Drug Discov Technol, 2020;17(2):248-260.
PMID: 30332967 DOI: 10.2174/1570163815666181017091655

INTRODUCTION: The primary aim of this study is to understand the binding of curcumin and its analogues to different PDE4 subtypes and identify the role of PDE4 subtype inhibition in the anti-inflammatory property of curcumin. Docking analysis has been used to acquire the above mentioned structural information and this has been further used for designing of curcumin derivatives with better anti-inflammatory activity.
MATERIALS AND METHODS: Curcumin and its analogues were subjected to docking using PDE4A, PDE4B, PDE4C and PDE4D as the targets. A data set comprising 18 analogues of curcumin, was used as ligands for docking of PDE4 subtypes. Curcumin was used as the standard for comparison. Docking was performed using AutoDock Vina 1.1.2 software integrated in LigandScout 4.1. During this process water molecules were removed from proteins, charges were added and receptor structures were minimised by applying suitable force fields. The docking scores were compared, and the selectivity of compounds for PDE4B over PDE4D was calculated as well.
RESULTS: All curcumin analogues used in the study showed good binding affinity with all PDE4 subtypes, with evident selectivity towards PDE4B subtype. Analogue A11 provides the highest binding affinity among all ligands.
CONCLUSION: Curcumin and analogues have moderate to strong affinity towards all PDE4 subtypes and have evident selectivity towards PDE4B. The Oxygen atom of the methoxy group plays a key role in PDE4B binding and any alterations could interfere with the binding. Tetrahydropyran side chain and heterocyclic rings are also suggested to be helpful in PDE4B binding.
Discovery of natural product inhibitors of phosphodiesterase 10A as novel therapeutic drug for schizophrenia using a multistep virtual screening

Al-Nema M, Gaurav A, Akowuah G

Comput Biol Chem, 2018 Dec;77:52-63.
PMID: 30240986 DOI: 10.1016/j.compbiolchem.2018.09.001

The major complaint that most of the schizophrenic patients' face is the cognitive impairment which affects the patient's quality of life. The current antipsychotic drugs treat only the positive symptoms without alleviating the negative or cognitive symptoms of the disease. In addition, the existing therapies are known to produce extrapyramidal side effects that affect the patient adherence to the treatment. PDE10A inhibitor is the new therapeutic approach which has been proven to be effective in alleviating the negative and cognitive symptoms of the disease. A number of PDE10A inhibitors have been developed, but no inhibitor has made it beyond the clinical trials so far. Thus, the present study has been conducted to identify a PDE10A inhibitor from natural sources to be used as a lead compound for the designing of novel selective PDE10A inhibitors. Ligand and structure-based pharmacophore models for PDE10A inhibitors were generated and employed for virtual screening of universal natural products database. From the virtual screening results, 37 compounds were docked into the active site of the PDE10A. Out of 37 compounds, three inhibitors showed the highest affinity for PDE10A where UNPD216549 showed the lowest binding energy and has been chosen as starting point for designing of novel PDE10A inhibitors. The structure-activity-relationship studies assisted in designing of selective PDE10A inhibitors. The optimization of the substituents on the phenyl ring resulted in 26 derivatives with lower binding energy with PDE10A as compared to the lead compound. Among these, MA 8 and MA 98 exhibited the highest affinity for PDE10A with binding energy (-10.90 Kcal/mol).
Designing of 2,3-dihydrobenzofuran derivatives as inhibitors of PDE1B using pharmacophore screening, ensemble docking and molecular dynamics approach

Al-Nema M, Gaurav A, Lee VS

Comput Biol Med, 2023 Apr 03;159:106869.
PMID: 37071939 DOI: 10.1016/j.compbiomed.2023.106869

In recent years, the PDE1B enzyme has become a desirable drug target for the treatment of psychological and neurological disorders, particularly schizophrenia disorder, due to the expression of PDE1B in brain regions involved in volitional behaviour, learning and memory. Although several inhibitors of PDE1 have been identified using different methods, none of these inhibitors has reached the market yet. Thus, searching for novel PDE1B inhibitors is considered a major scientific challenge. In this study, pharmacophore-based screening, ensemble docking and molecular dynamics simulations have been performed to identify a lead inhibitor of PDE1B with a new chemical scaffold. Five PDE1B crystal structures have been utilised in the docking study to improve the possibility of identifying an active compound compared to the use of a single crystal structure. Finally, the structure-activity- relationship was studied, and the structure of the lead molecule was modified to design novel inhibitors with a high affinity for PDE1B. As a result, two novel compounds have been designed that exhibited a higher affinity to PDE1B compared to the lead compound and the other designed compounds.
Clinical and Radiographic Evaluation of Autologous Platelet-Rich Fibrin With or Without Demineralized Bone Matrix in the Treatment of Grade II Furcation Defects

Patel B, Joshi S, Nagrani T, Girdhar GA, Patel H, Sinha S, et al.

Cureus, 2023 Aug;15(8):e44394.
PMID: 37654905 DOI: 10.7759/cureus.44394

Introduction This study aims to differentiate the employment of demineralized bone matrix (DMBM; Osseograft, Advanced Biotech Products (P) Ltd, Chennai, India) and platelet-rich fibrin (PRF) alone to a composite graft consisting of both materials in the surgical actions toward the anomalies of the human periodontal furcation imperfection. Methods In a split-mouth study, 30 patients with mandibular molars affected by the furcation were allocated without conscious choice to test (PRF + DMBM, n = 30) or control (PRF, n = 30) categories. At the starting point, three months after surgery, and six months later, the following modifiable factors were evaluated: probing pocket depth (PPD), full-mouth plaque scores, full-mouth gingival scores, radiographic defect depth, relative vertical clinical attachment level (RVCAL), and relative horizontal clinical attachment level (RHCAL). Results Results at three and six months demonstrated substantial differences between baseline values for both treatment methods in clinical and X-ray imaging appraisal. Nonetheless, the PRF/DMBM group manifests statistically significantly soaring changes observed in comparison to the PRF group. Overall, the probing depth (PD) in the test site was significantly lower than that in the control site, showing a reduction of 68% (95% CI=41%, 95%, p<0.001). Conclusion Clinical indications significantly improved with PRF and DMBM combined instead of PRF alone. On radiographs, the test group also showed higher bone fill.
Non-cancer to anti-cancer: investigation of human ether-a-go-go-related gene potassium channel inhibitors as potential therapeutics

Patil VM, Gaurav A, Garg P, Masand N

J Egypt Natl Canc Inst, 2021 Nov 08;33(1):33.
PMID: 34746987 DOI: 10.1186/s43046-021-00091-3

BACKGROUND: The expression of hERG K+ channels is observed in various cancer cells including epithelial, neuronal, leukemic, and connective tissue. The role of hERG potassium channels in regulating the growth and death of cancer cells include cell proliferation, survival, secretion of proangiogenic factors, invasiveness, and metastasis.
METHODS: In the reported study, an attempt has been made to investigate some non-cancer hERG blockers as potential cancer therapeutics using a computational drug repurposing strategy. Preliminary investigation for hERG blockers/non-blockers has identified 26 potential clinically approved compounds for further studies using molecular modeling.
RESULTS: The interactions at the binding pockets have been investigated along with the prioritization based on the binding score. Some of the identified potential hERG inhibitors, i.e., Bromocriptine, Darglitazone, and Troglitazone, have been investigated to derive the mechanism of cancer inhibition.
CONCLUSIONS: The proposed mechanism for anti-cancer properties via hERG blocking for some of the potential compounds is required to be explored using other experimental methodologies. The drug repurposing approach applied to investigate anti-cancer therapeutics may direct to provide a therapeutic solution to late-stage cancer and benefit a significant population of patients.
Computational Approaches in the Discovery and Development of Therapeutic and Prophylactic Agents for Viral Diseases

Gaurav A, Agrawal N, Al-Nema M, Gautam V

Curr Top Med Chem, 2022;22(26):2190-2206.
PMID: 36278463 DOI: 10.2174/1568026623666221019110334

Over the last two decades, computational technologies have played a crucial role in antiviral drug development. Whenever a virus spreads and becomes a threat to global health, it brings along the challenge of developing new therapeutics and prophylactics. Computational drug and vaccine discovery has evolved quickly over the years. Some interesting examples of computational drug discovery are anti-AIDS drugs, where HIV protease and reverse transcriptase have been targeted by agents developed using computational methods. Various computational methods that have been applied to anti-viral research include ligand-based methods that rely on known active compounds, i.e., pharmacophore modeling, machine learning or classical QSAR; structure-based methods that rely on an experimentally determined 3D structure of the targets, i.e., molecular docking and molecular dynamics and methods for the development of vaccines such as reverse vaccinology; structural vaccinology and vaccine epitope prediction. This review summarizes these approaches to battle viral diseases and underscores their importance for anti-viral research. We discuss the role of computational methods in developing small molecules and vaccines against human immunodeficiency virus, yellow fever, human papilloma virus, SARS-CoV-2, and other viruses. Various computational tools available for the abovementioned purposes have been listed and described. A discussion on applying artificial intelligence-based methods for antiviral drug discovery has also been included.
Structure-based design of selective phosphodiesterase 4B inhibitors based on ginger phenolic compounds

Xing M, Akowuah GA, Gautam V, Gaurav A

J Biomol Struct Dyn, 2017 Oct;35(13):2910-2924.
PMID: 27608741 DOI: 10.1080/07391102.2016.1234417

Phosphodiesterase 4 (PDE4) has been established as a drug target for inflammatory diseases of respiratory tract like asthma and chronic obstructive pulmonary disease. The selective inhibitors of PDE4B, a subtype of PDE4, are devoid of adverse effects like nausea and vomiting commonly associated with non-selective PDE4B inhibitors. This makes the development of PDE4B subtype selective inhibitors a desirable research goal. Thus, in the present study, molecular docking, molecular dynamic simulations and binding free energy were performed to explore potential selective PDE4B inhibitors based on ginger phenolic compounds. The results of docking studies indicate that some of the ginger phenolic compounds demonstrate higher selective PDE4B inhibition than existing selective PDE4B inhibitors. Additionally, 6-gingerol showed the highest PDE4B inhibitory activity as well as selectivity. The comparison of binding mode of PDE4B/6-gingerol and PDE4D/6-gingerol complexes revealed that 6-gingerol formed additional hydrogen bond and hydrophobic interactions with active site and control region 3 (CR3) residues in PDE4B, which were primarily responsible for its PDE4B selectivity. The results of binding free energy demonstrated that electrostatic energy is the primary factor in elucidating the mechanism of PDE4B inhibition by 6-gingerol. Dynamic cross-correlation studies also supported the results of docking and molecular dynamics simulation. Finally, a small library of molecules were designed based on the identified structural features, majority of designed molecules showed higher PDE4B selectivity than 6-gingerol. These results provide important structural features for designing new selective PDE4B inhibitors as anti-inflammatory drugs and promising candidates for synthesis and pre-clinical pharmacological investigations.
Effect of processing methods on xylitol-starch base co-processed adjuvant for orally disintegrating tablet application

Bin LK, Helaluddin ABM, Islam Sarker MZ, Mandal UK, Gaurav A

Pak J Pharm Sci, 2020 Mar;33(2):551-559.
PMID: 32276897

Orally disintegrating tablet (ODT) is a friendly dosage form that requires no access to water and serves as a solution to non-compliance. There are many co-processed adjuvants available in the market. However, there is no single product possesses all the ideal characteristics such as good compressibility, fast disintegration and good palatability for ODT application. The aim of this research was to produce a xylitol-starch base co-processed adjuvant which is suitable for ODT application. Two processing methods namely wet granulation and freeze drying were used to compare the characteristics of co-processed adjuvant comprising of xylitol, starch and crospovidone XL-10 mixed at various ratios. The co-processed excipients were compressed into ODT and physically characterized for powder flow, particle size, hardness, thickness, weight, friability, in-vitro disintegration time and in-situ disintegration time, lubricant sensitivity, dilution potential, Fourier transform infrared spectroscopy, scanning electronic microscopy and x-ray diffraction analysis. Formulation F6 was selected as the optimum formulation due to the fastest in-vitro (135.33±11.52 s) and in-situ disintegration time (88.67±13.56s) among all the formulations (p<0.05). Increase in starch component decreases disintegration time of ODT. The powder flow fell under the category of fair flow. Generally, it was observed that freeze drying method produced smaller particle size granules compared to wet granulation method. ODT produced from freeze drying method had shorter disintegration time compared to ODT from wet granulation batch. In conclusion, a novel co-processed excipient comprised of xylitol, starch and crospovidone XL-10, produced using freeze drying method with fast disintegration time, good compressibility and palatability was developed and characterized. The co-processed excipient is suitable for ODT application.
Synthesis of 2-(2-oxo-2H-chromen-4-yl)acetamides as potent acetylcholinesterase inhibitors and molecular insights into binding interactions

Kara J, Suwanhom P, Wattanapiromsakul C, Nualnoi T, Puripattanavong J, Khongkow P, et al.

Arch Pharm (Weinheim), 2019 Jul;352(7):e1800310.
PMID: 31125474 DOI: 10.1002/ardp.201800310

Sixteen novel coumarin-based compounds are reported as potent acetylcholinesterase (AChE) inhibitors. The most active compound in this series, 5a (IC50 0.04 ± 0.01 µM), noncompetitively inhibited AChE with a higher potency than tacrine and galantamine. Compounds 5d, 5j, and 5 m showed a moderate antilipid peroxidation activity. The compounds showed cytotoxicity in the same range as the standard drugs in HEK-293 cells. Molecular docking demonstrated that 5a acted as a dual binding site inhibitor. The coumarin moiety occupied the peripheral anionic site and showed π-π interaction with Trp278. The tertiary amino group displayed significant cation-π interaction with Phe329. The aromatic group showed π-π interaction with Trp83 at the catalytic anionic site. The long chain of methylene lay along the gorge interacting with Phe330 via hydrophobic interaction. Molecular docking was applied to postulate the selectivity toward AChE of 5a in comparison with donepezil and tacrine. Structural insights into the selectivity of the coumarin derivatives toward huAChE were explored by molecular docking and 3D QSAR and molecular dynamics simulation for 20 ns. ADMET analysis suggested that the 2-(2-oxo-2H-chromen-4-yl)acetamides showed a good pharmacokinetic profile and no hepatotoxicity. These coumarin derivatives showed high potential for further development as anti-Alzheimer agents.
Fulltext Evaluation of the acute oral toxicity and antipsychotic activity of a dual inhibitor of PDE1B and PDE10A in rat model of schizophrenia

Al-Nema M, Gaurav A, Lee MT, Okechukwu P, Nimmanpipug P, Lee VS

PLoS One, 2022;17(12):e0278216.
PMID: 36454774 DOI: 10.1371/journal.pone.0278216

Phosphodiesterase 1B (PDE1B) and PDE10A are dual-specificity PDEs that hydrolyse both cyclic adenosine monophosphate and cyclic guanosine monophosphate, and are highly expressed in the striatum. Several reports have suggested that PDE10A inhibitors may present a promising approach for the treatment of positive symptoms of schizophrenia, whereas PDE1B inhibitors may present a novel mechanism to modulate cognitive deficits. Previously, we have reported a novel dual inhibitor of PDE1B and PDE10A, compound 2 [(3-fluorophenyl)(2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone] which has shown inhibitory activity for human recombinant PDE1B and PDE10A in vitro. In the present study, the safety profile of compound 2 has been evaluated in rats in the acute oral toxicity study, as well as; the antipsychotic-like effects in the rat model of schizophrenia. Compound 2 was tolerated up to 1 g/kg when administered at a single oral dose. Additionally, compound 2 has strongly suppressed ketamine-induced hyperlocomotion, which presented a model for the positive symptoms of schizophrenia. It has also shown an ability to attenuate social isolation induced by chronic administration of ketamine and enhanced recognition memory of rats in the novel object recognition test. Altogether, our results suggest that compound 2 represents a promising therapy for the treatment of the three symptomatic domains of schizophrenia.
Fulltext Comparative Studies of Palmatine with Metformin and Glimepiride on the Modulation of Insulin Dependent Signaling Pathway In Vitro, In Vivo & Ex Vivo

Nwabueze OP, Sharma M, Balachandran A, Gaurav A, Abdul Rani AN, Małgorzata J, et al.

Pharmaceuticals (Basel), 2022 Oct 25;15(11).
PMID: 36355489 DOI: 10.3390/ph15111317

(1) Insulin resistance, a symptom of type 2 diabetes mellitus (T2DM), is caused by the inactivation of the insulin signaling pathway, which includes IRS-PI3K-IRS-1-PKC-AKT2 and GLUT4. Metformin (biguanide) and glimepiride (sulfonylurea) are both drugs that are derivatives of urea, and they are widely used as first-line drugs for the treatment of type 2 diabetes mellitus. Palmatine has been previously reported to possess antidiabetic and antioxidant properties. (2) The current study compared palmatine to metformin and glimepiride in a type 2 diabetes model for ADME and insulin resistance via the PI3K/Akt/GLUT4 signaling pathway: in vitro, in vivo, ex vivo, and in silico molecular docking. (3) Methods: Differentiated L6 skeletal muscle cells and soleus muscle tissue were incubated in standard tissue culture media supplemented with high insulin and high glucose as a cellular model of insulin resistance, whilst streptozotocin (STZ)-induced Sprague Dawley rats were used as the diabetic model. The cells/tissue/animals were treated with palmatine, while glimepiride and metformin were used as standard drugs. The differential gene expression of PI3K, IRS-1, PKC-α, AKT2, and GLUT4 was evaluated using qPCR. (4) Results: The results revealed that the genes IRS-PI3K-IRS-1-PKC-AKT2 were significantly down-regulated, whilst PKC-α was upregulated significantly in both insulin-resistant cells and tissue animals. Interestingly, palmatine-treated cells/tissue/animals were able to reverse these effects. (5) Conclusions: Palmatine appears to have rejuvenated the impaired insulin signaling pathway through upregulation of the gene expression of IRS-1, PI3K, AKT2, and GLUT4 and downregulation of PKC-expression, according to in vitro, in vivo, and ex vivo studies.

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