scholarly journals Investigation of Hypoglycemic Peptides Derived from Conserved Regions of adMc1 to Reveal Their Antidiabetic Activities

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Hafiza Salaha Mahrosh ◽  
Rizwan Mehmood ◽  
Shazia Anwer Bukhari ◽  
Gulnaz Afzal ◽  
Rawaba Arif
Keyword(s):  
Gastrointestinal Manifestations ◽  
Receptor Proteins ◽  
Drug Candidates ◽  
Conserved Regions ◽  
Dpp Iv ◽  
Novel Approach ◽  
Chronic Disorder ◽  
Native Populations ◽  
Docking Approach ◽  
Combinational Therapies

Diabetes mellitus is the most common chronic disorder and leading cause of renal, neurological, and gastrointestinal manifestations in developed and developing countries. Despite of many drugs and combinational therapies, the complications of diabetes are still listed due to severe consequences of those drugs. In past few years, plant-derived drugs draw special attention due to their higher efficacy and fewer side-effects. Momordica charantia also known as bitter melon is referred as an antidiabetic and hypoglycemic plant in native populations of Asia and East Africa. In current study, an in silico approach was used to evaluate the interactions and binding patterns of plant-derived peptides devised from a hypoglycemic protein adMc1 of M. charantia as potential inhibitor of DPP-IV, SGLT1, and GLUT2 receptor proteins. The study has described a novel approach to investigate hypoglycemic peptides to cure diabetes. A total of eighty tetra-, penta-, and hexapeptides were devised from conserved regions of adMc1 homologs. The molecular docking approach using MOE software was employed to reveal inhibiting potentials of devised peptides against three selected proteins. Out of 30 shortlisted ligands six peptides (i.e. SMCG, DECC, TTIT, RTTI, ARNL and TVEV) accomplished the criteria of being good drug candidates against selected receptor proteins following the drugability assessment test. The overall results are acceptable on the basis of ADMET profiling for being good drug candidates against selected proteins.

scholarly journals Development of intravenously administered synthetic RNA virus immunotherapy for the treatment of cancer

2021 ◽  
Author(s):  
Edward Kennedy ◽  
Agnieszka Denslow ◽  
Jacqueline Hewett ◽  
Lingxin Kong ◽  
Ana De Almeida ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Rna Virus ◽  
Neutralizing Antibody ◽  
Repeated Administration ◽  
Oncolytic Viruses ◽  
Drug Candidates ◽  
Novel Approach ◽  
Coxsackievirus A21 ◽  
Anti Tumor Activity

Abstract Oncolytic viruses (OVs) are an emerging therapeutic approach for the treatment of cancer. Clinical benefit has been demonstrated for intratumoral administration, but the therapeutic effectiveness of intravenous delivery has been limited by neutralizing antibody responses against the virus. To circumvent this limitation, we developed Synthetic RNA viruses, a novel approach for intravenous and repeated administration of OVs, consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21 (CVA21), we demonstrate vRNA delivery, viral replication, spread, and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. Synthetic-SVV replication in tumors promoted immune cell infiltration and enhanced anti-tumor activity in combination with anti-PD-1 checkpoint inhibitor. Altogether, the Synthetic RNA virus platform provides an innovative approach that enables repeat intravenous administration of viral immunotherapy.

An insight into anti-arthritic property of phytochemicals against Rheumatoid arthritis using molecular modelling and docking approach

2021 ◽  
Vol 16 (12) ◽  
pp. 185-195
Author(s):  
Bharathi Nathan ◽  
Sudheer M.M. Mohammed
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Targets ◽  
Joint Inflammation ◽  
Binding Energies ◽  
Multiple Drug ◽  
Matrix Metalloproteinase 3 ◽  
Drug Candidates ◽  
Docking Tool ◽  
Docking Approach ◽  
Interleukin 23

Arthritis literally refers “joint inflammation”, it is a condition where one or more joints are inflamed. More than 100 different types of Arthritis were identified, most common types are rheumatoid arthritis and osteoarthritis. The present study mainly focuses on the development of the novel phytochemical inhibitors against rheumatoid arthritis and osteoarthritis using an integrative cheminformatics drug discovery platform. In this study, we identified potential 405 phytochemical drug candidates, screened against eight selected targets of rheumatoid arthritis and osteoarthritis using molecular docking tool AutoDock. Three phytochemicals Withanolide, Diosgenin and bamyrin exhibited promising binding towards multiple drug targets selected for this study. When comparing with the binding between reference drugs, withanolide showed highest activity against Interleukin-23, Matrix metalloproteinase-3 and Interleukin 8 with binding energies -11.6, -9.4 and -8.3 kcal/mol respectively. Diosgenin also exhibited best activity against three targets that were Interleukin-23, JNK alpha and MMP-3 with -11.3, -10.4, -9.5 kcal/mol binding energies respectively. This study may be important contributing factor to develop new therapeutic drugs for rheumatoid arthritis and osteoarthritis.

scholarly journals Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

2020 ◽  
Author(s):  
Mahmudul Hasan ◽  
Md Sorwer Alam Parvez ◽  
Kazi Faizul Azim ◽  
Abdus Shukur Imran ◽  
Topu Raihan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Repurposing ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Drug Candidates ◽  
Target Drug ◽  
Global Pandemic ◽  
Main Protease ◽  
Docking Approach ◽  
Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

scholarly journals Fi-score: a novel approach to characterise protein topology and aid in drug discovery studies

2020 ◽  
Author(s):  
Austė Kanapeckaitė ◽  
Claudia Beaurivage ◽  
Matthew Hancock ◽  
Erik Verschueren
Keyword(s):  
Dihedral Angle ◽  
Target Selection ◽  
Gaussian Mixture Models ◽  
Drug Repurposing ◽  
Gaussian Mixture ◽  
Rational Drug Design ◽  
Drug Candidates ◽  
Novel Approach ◽  
Protein Fingerprinting ◽  
Rational Drug

AbstractTarget evaluation is at the centre of rational drug design and biologics development. In order to successfully engineer antibodies, T-cell receptors or small molecules it is necessary to identify and characterise potential binding or contact sites on therapeutically relevant target proteins. Currently, there are numerous challenges in achieving a better docking precision as well as characterising relevant sites. We devised a first-of-its-kind in silico protein fingerprinting approach based on dihedral angle and B-factor distribution to probe binding sites and sites of structural importance. In addition, we showed that the entire protein regions or individual structural subsets can be profiled using our derived fi-score based on amino acid dihedral angle and B-factor distribution. We further described a method to assess the structural profile and extract information on sites of importance using machine learning Gaussian mixture models. In combination, these biophysical analytical methods could potentially help to classify and systematically analyse not only targets but also drug candidates that bind to specific sites which would greatly improve pre-screening stage, target selection and drug repurposing efforts in finding other matching targets.

scholarly journals Limited thermal plasticity and geographic divergence in the ovipositor of Drosophila suzukii

2019 ◽  
Author(s):  
Ceferino Varón-González ◽  
Antoine Fraimout ◽  
Arnaud Delapré ◽  
Vincent Debat ◽  
Raphaël Cornette
Keyword(s):  
Geographic Origin ◽  
Invasion Success ◽  
Effect Of Temperature ◽  
Stabilizing Selection ◽  
Geographic Differentiation ◽  
Drosophila Suzukii ◽  
Thermal Plasticity ◽  
Novel Approach ◽  
Combined Use ◽  
Native Populations

AbstractPhenotypic plasticity has been repeatedly suggested to facilitate adaptation to new environmental conditions, as in invasions. Here we investigate this possibility by focusing on the worldwide invasion of Drosophila suzukii: an invasive species that has rapidly colonized all continents over the last decade. This species is characterized by a highly developed ovipositor, allowing females to lay eggs through the skin of ripe fruits. Using a novel approach based on the combined use of SEM and photogrammetry, we quantified the ovipositor size and 3D shape, contrasting invasive and native populations raised at three different developmental temperatures. We found a small but significant effect of temperature and geographic origin on the ovipositor shape, showing the occurrence of both geographic differentiation and plasticity to temperature. The shape reaction norms are in turn strikingly similar among populations, suggesting very little difference in shape plasticity among invasive and native populations, and therefore rejecting the hypothesis of a particular role for plasticity of the ovipositor in the invasion success. Overall, the ovipositor shape seems to be a fairly robust trait, indicative of stabilizing selection. The large performance spectrum rather than the flexibility of the ovipositor would thus contribute to the success of D. suzukii worldwide invasion.

scholarly journals Limited thermal plasticity and geographical divergence in the ovipositor of Drosophila suzukii

2020 ◽  
Vol 7 (1) ◽  
pp. 191577
Author(s):  
Ceferino Varón-González ◽  
Antoine Fraimout ◽  
Arnaud Delapré ◽  
Vincent Debat ◽  
Raphaël Cornette
Keyword(s):  
Three Dimensional ◽  
Invasion Success ◽  
Effect Of Temperature ◽  
Stabilizing Selection ◽  
Drosophila Suzukii ◽  
Thermal Plasticity ◽  
Novel Approach ◽  
Combined Use ◽  
Native Populations ◽  
Dimensional Shape

Phenotypic plasticity has been repeatedly suggested to facilitate adaptation to new environmental conditions, as in invasions. Here, we investigate this possibility by focusing on the worldwide invasion of Drosophila suzukii : an invasive species that has rapidly colonized all continents over the last decade. This species is characterized by a highly developed ovipositor, allowing females to lay eggs through the skin of ripe fruits. Using a novel approach based on the combined use of scanning electron microscopy and photogrammetry, we quantified the ovipositor size and three-dimensional shape, contrasting invasive and native populations raised at three different developmental temperatures. We found a small but significant effect of temperature and geographical origin on the ovipositor shape, showing the occurrence of both geographical differentiation and plasticity to temperature. The shape reaction norms are in turn strikingly similar among populations, suggesting very little difference in shape plasticity among invasive and native populations, and therefore rejecting the hypothesis of a particular role for the plasticity of the ovipositor in the invasion success. Overall, the ovipositor shape seems to be a fairly robust trait, indicative of stabilizing selection. The large performance spectrum rather than the flexibility of the ovipositor would thus contribute to the success of D. suzukii worldwide invasion.

Emerging Drug Candidates of Dipeptidyl Peptidase IV (DPP IV) Inhibitor Class for the Treatment of Type 2 Diabetes

2009 ◽  
Vol 10 (1) ◽  
pp. 71-87 ◽  
Author(s):  
Rajesh Gupta ◽  
Sameer Walunj ◽  
Ranjeet Tokala ◽  
Kishore Parsa ◽  
Santosh Singh ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Drug Candidates ◽  
Dpp Iv

scholarly journals Orally administered branaplam does not impact neurogenesis in juvenile mice, rats, and dogs

Biology Open ◽  
2021 ◽  
Author(s):  
Diethilde Theil ◽  
Reginald Valdez ◽  
Katy Darribat ◽  
Arno Doelemeyer ◽  
Rajeev Sivasankaran ◽  
...  
Keyword(s):  
Image Analysis ◽  
Active Drug ◽  
Muscular Atrophy ◽  
Histopathological Examination ◽  
Brain Regions ◽  
Quantitative Image Analysis ◽  
Drug Candidates ◽  
Novel Approach ◽  
Quantitative Image ◽  
Calbindin D28k

Branaplam is a therapeutic agent currently in clinical development for the treatment of infants with type 1 spinal muscular atrophy (SMA). Since preclinical studies showed that branaplam had cell-cycle arrest effects; we sought to determine whether branaplam may affect postnatal cerebellar development and brain neurogenesis. Here, we describe a novel approach for developmental neurotoxicity testing (DNT) of a central nervous system (CNS) active drug. The effects of orally administered branaplam were evaluated in the SMA neonatal mouse model (SMN▵7), and in juvenile Wistar Hanover rats and Beagle dogs. Histopathological examination and complementary immunohistochemical studies focused on areas of neurogenesis in the cerebellum (mice, rats, and dogs), and the subventricular zone of the striatum and dentate gyrus (rats and dogs) using antibodies directed against Ki67, phosphorylated histone H3, cleaved caspase-3, and glial fibrillary acidic protein. Additionally, image analysis based quantification of calbindin-D28k and Ki67 was performed in rats and dogs. The patterns of cell proliferation and apoptosis, and neural migration and innervation in the cerebellum and other brain regions of active adult neurogenesis did not differ between branaplam- and control-treated animals. Quantitative image analysis did not reveal any changes in calbindin-D28k and Ki67 expression in rats and dogs. The data show that orally administered branaplam has no impact on neurogenesis in juvenile animals. Application of selected immunohistochemical stainings in combination with quantitative image analysis on a few critical areas of postnatal CNS development offer a reliable approach to assess DNT of CNS-active drug candidates in juvenile animal toxicity studies.

scholarly journals Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

2020 ◽  
Author(s):  
Mahmudul Hasan ◽  
Md Sorwer Alam Parvez ◽  
Kazi Faizul Azim ◽  
Abdus Shukur Imran ◽  
Topu Raihan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Repurposing ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Drug Candidates ◽  
Target Drug ◽  
Global Pandemic ◽  
Main Protease ◽  
Docking Approach ◽  
Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

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