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- Volume 19, Issue 10, 2022
Letters in Drug Design & Discovery - Volume 19, Issue 10, 2022
Volume 19, Issue 10, 2022
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Recent Advances in Drug Design and Delivery Across Biological Barriers Using Computational Models
Authors: Vanshita, Akash Garg and Hitesh K. DewanganThe systemic delivery of pharmacological substances generally exhibits several significant limitations associated with the bio-distribution of active drugs in the body. Human body’s defense mechanisms have been found to become impediments to drug delivery. Various technologies have evolved to overcome these limitations, including computational approaches and advanced drug delivery. As the body of a human has evolved to defend itself from hostile biological as well as chemical invaders, the biological barriers, such as ocular barriers, blood-brain barriers, intestinal and skin barriers, also limit the passage of drugs across desired sites. Therefore, efficient delivery remains an utmost challenge for researchers and scientists. The present review focuses on the techniques to deliver the drugs with efficient therapeutic efficacy at the targeted sites. This review article provides an insight into the main biological barriers along with the application of computational or numerical methods to deal with different barriers by determining the drug flow, temperature and various other parameters. It also summarizes the advanced implantable drug delivery systems to circumvent the inherent resistance exhibited by these biological barriers, and in turn, to improve the drug delivery process.
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Screening of Natural Compounds Against SOD1 as a Therapeutic Target for Amyotrophic Lateral Sclerosis
Authors: Sonu Pahal, Amit Chaudhary and Sangeeta SinghBackground: Amyotrophic lateral sclerosis (ALS) is an uncommon and progressive neurological illness that predominantly includes the neurons liable for voluntary muscular activities. Starting from weakness or stiffness in muscles, this gradually exploits the strength and ability to speak, eat, move, and even breathe. Its exact mechanism is still not clear, but mutations in the SOD1 gene have been reported to cause ALS, and some studies also found involvement of SOD1 overexpression in the pathogenesis of ALS. As of now, there is no remedy available for its cure. Objective: The objective of this study is to identify the potential inhibitors for wild type 1HL5, l113T mutant, and A4V mutant of SOD1 (Superoxide Dismutase 1) protein. Methods: In this study, in silico approaches like virtual screening, molecular docking, pharmacokinetic parameters study, and molecular dynamics simulation were used to identify the best potential inhibitors against wild type and mutant SOD1 protein. Results: On the basis of binding affinity and binding energy, the top three compounds ZINC000095486263, ZINC000095485989, and ZINC000028462577 were observed as the best compounds. In the case of 1HL5, ZINC000095486263 had the highest binding affinity with docking score - 10.62 Kcal/mol, 1UXM with ZINC000095485989 had the highest docking score -12.03 Kcal/mol, and 4A7V with ZINC000028462577 was found -11.72 Kcal/mol. Further, Molecular Dynamic Simulations (MDS) results showed that the ZINC000095486263, ZINC000095485989, and ZINC000095485956 compounds were formed a stable complex with 1HL5, 1UXM, and 4A7V respectively. Conclusion: After analyzing the results, we hereby conclude that natural compounds such as ZINC000095486263, ZINC000095485989, and ZINC000095485956 could be used as a potential inhibitor of 1HL5, 1UXM, and 4A7V respectively for ALS treatment and could be used as a drug. Further, In vivo/vitro study of these compounds could be a future direction in the field of drug discovery.
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Thiamine: A Natural Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ) Activator
Background: There has been increasing evidence of the correlation between thiamine deficiency and type 2 diabetes (T2D). T2D is a condition in which an individual’s insulin sensitivity is highly compromised. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a ligand-activated transcription factor etiologically relevant to T2D. We hypothesized that thiamine could be a PPAR-γ ligand and thus activate PPAR-γ and ameliorate T2D. Objective: This study aims to establish thiamine as a PPAR-γ ligand via molecular docking and dynamics simulations (MDS) and thiamine’s ability to induce adipogenesis while upregulating PPAR-γ and AP-2 genes using in vitro assays. Methods: Thiamine/PPAR-γ binding was studied using Schrödinger’s Glide. The bound complex was simulated in the OPLS 2005 force field using Desmond. 3T3-L1 preadipocyte cells were differentiated in the presence of thiamine and rosiglitazone and stained with Oil Red O. Nuclear protein from the differentiated cells was used to study the binding of the PPAR-γ response element (PPRE) using an ELISA-based assay. mRNA from differentiated cells was used to study the expression of genes using quantitative RTPCR. Results: In silico docking shows that thiamine binds with PPAR-γ. MDS indicate that the interactions between thiamine and PPAR-γ are stable over a significant period. Thiamine induces the differentiation of 3T3-L1 preadipocytes in a dose-dependent manner and enhances the PPRE-binding activity of PPAR-γ. Thiamine treatment significantly increases the mRNA levels of PPAR-γ and AP-2 genes. Conclusion: Our results show that thiamine is a PPAR-γ ligand. Animal studies and clinical trials are required to corroborate the results obtained.
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Design and Analysis of Pharmacokinetics, Pharmacodynamics and Toxicological Analysis of Cannabidiol Analogs using In Silico Tools
Authors: Carlos R. Mendes Júnior and Eduardo Damasceno CostaBackground: Cannabidiol (CBD), a non-psychoactive phytocannabinoid from Cannabis Sativa, has become an interesting option for medicinal chemists in the development of new drug candidates. Objective: This study aims to propose analogs with therapeutic potential from the CBD scaffold. Methods: The 16 analogs proposed were designed using the PubChem Sketcher V. 2.4® software. Already, CBD analogs were subjected to different in silico tools, such as Molinspiration®; SwissADME®; SwissTargetPrediction®, and OSIRIS Property Explorer®. Results and Discussion: The screening of CBD analogs carried out in this study showed compounds 9 and 16 with a good affinity for interactions with CB1 and CB2 receptors. Pharmacokinetic data showed that these two compounds have good oral absorption. Finally, in silico toxicity data showed that these compounds pose no risk of a toxic event in humans. Conclusion: CBD analogs 9 and 16 would have a better profile of drug candidates to be further tested in vitro and in vivo models.
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Pharmacophore Modelling and Virtual Screening Studies for the Discovery of Natural Product-based PDE 3/4 Dual Inhibitors for COPD
Authors: Tan X. Hui, Lim Jia Le and Anand GauravBackground: Chronic Obstructive Pulmonary Disorder (COPD) is a chronic and progressive lung disease with a steady increase in prevalence over the recent years. Current treatment options of COPD are aimed at symptomatic relief without the ability to cure COPD, and certain corticosteroid treatments cause patients to be susceptible to infections. Newer studies have hinted that PDE3/4 dual inhibitors may produce a higher efficacy and better safety profile compared to current alternatives. These novel inhibitors may potentially improve the control of COPD exacerbation without increasing the risk of infections. Thus, our study aimed to identify and refine natural compounds with PDE3/4 dual inhibitory activities through molecular modelling techniques. Methods: A two-sided approach through ligand-based and structure-based pharmacophore modelling was employed, followed by virtual screening and molecular docking to identify lead compounds with PDE3/4 dual inhibition activity. Results: Pharmacophore-based screening of Universal Natural Products Database (UNPD) resulted in the identification of one compound for each pharmacophore model, namely UNPD1558 and UNPD139455, with high binding affinities towards both PDE3B and PDE4B. The two compounds were subsequently docked with PDE3B and PDE4B to study their interactions with the active site residues. Structural modifications of the compounds were proposed based on the docking results to optimise their binding affinity and physicochemical properties. Conclusion: Compound 25a4 and compound 28, which were designed based on the structures of UNPD1558 and UNPD139455, respectively, showed an improved binding affinity for both PDE3B and PDE4B. These lead compounds showed promising results as drug candidates, and their PDE3/4 dual inhibitory properties should be further investigated through in vivo and in vivo studies.
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Novel S-Mercaptotriazolebenzothiazole-Based Derivatives as Antimicrobial Agents: Design, Synthesis, and In Vitro Evaluation
Background: The search for novel antimicrobial agents effective against the emerging resistant pathogenic microorganisms to the currently used drugs is a substantial need. Herein, a novel series of compounds bearing a benzothiazolotriazole scaffold was synthesized and evaluated as potential antimicrobial agents against a panel of gram +ve, gram -ve bacteria, and fungi species. Methods: The new compounds were synthesized via hybridization between the benzothiazolotriazole scaffold and thiadiazole ring or various substituted aromatic moieties using the tethering technique in drug discovery. Results: The in vitro results revealed that these compounds have significant antifungal activity rather than antibacterial potential due to their high similarity with tricyclazole. Compound 7b bearing bromo-phenyl moiety was the most potent derivative with an MIC value of 8 μg/mL against Candida albicans and Penicillium chrysogenum. Conclusion: Collectively, benzothiazolotriazole-based derivatives are good antifungal leads and should be further actively pursued to expand treatment options for systemic and topical fungal infections.
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Favorable Aspects of Silymarin in Linezolid Treatment Against Diabetic Methicillin-Resistant Staphylococcus aureus (MRSA) Infected Rats
Authors: Lalitha Vivekanandan, Sengottuvelu Singaravel and Sivakumar ThangavelBackground: Linezolid used for diabetic methicillin-resistant Staphylococcus aureus (MRSA) infections is limited due to hepatotoxicity, lactic acidosis, anemia, and oxidative stress induced by diabetes and linezolid therapy. Silymarin is a hepatoprotective, antioxidant, antibacterial, and antidiabetic. Objective: The research investigated the role of silymarin in linezolid treatment against MRSA-infected diabetic rats. Methods: Type 2 diabetes mellitus (T2DM) was induced by a high-fat diet (58% calories fat) for 2 weeks, followed by a single intraperitoneal injection of streptozotocin (STZ) 35 mg/kg into Wistar rats. The diabetic rats were rendered neutropenic and subcutaneously injected with 106 CFU/ml of MRSA. Linezolid and silymarin were administered orally at a dose of 50 mg/kg twice daily for 14 days. The bacterial load/abscess, hematological, biochemical, enzymatic parameters, antioxidants, and histopathological studies were performed on the 42nd day. Results: The MRSA was confirmed by PCR assay. The minimum inhibitory concentration of linezolid was found to be 0.5-2 μg/ml. The linezolid treated MRSA infected diabetic rats showed 9.69 x 103 CFU / abscess bacterial count, decreased intestinal alkaline phosphatase (IAP), RBC, antioxidants, elevated lactate, and liver markers than diabetic rats. The silymarin treatment showed a decrease in the bacterial count (2.98 x 103CFU / abscess), serum lactate, liver markers, increased IAP levels, and antioxidants in linezolid treated diabetic infected rats. Conclusion: The research concluded that silymarin could be a better herbal therapeutic agent that attenuated diabetic and linezolid induced complications in MRSA-infected diabetic rats.
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Volumes & issues
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Volume 21 (2024)
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Volume 20 (2023)
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Volume 19 (2022)
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Volume 18 (2021)
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Volume 17 (2020)
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Volume 16 (2019)
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Volume 15 (2018)
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Volume 14 (2017)
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Volume 13 (2016)
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Volume 12 (2015)
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Volume 11 (2014)
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Volume 10 (2013)
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Volume 9 (2012)
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Volume 8 (2011)
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Volume 7 (2010)
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Volume 6 (2009)
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Volume 5 (2008)
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Volume 4 (2007)
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Volume 3 (2006)
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Volume 2 (2005)
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Volume 1 (2004)