Loading

JSM Chemistry

Identification of Small-Sugars as Modulators of NeurotrophinReceptor Interactions

Research Article | Open Access Volume 9 | Issue 1 |

  • 1. Department of Morphophysiology, The Royal and Pontificial Major University of Saint Francis Xavier, Bolivia
  • 2. Institute of General Organic Chemistry, Department of Bio-organic Chemistry, Spain
  • 3. San Francisco Xavier Royal and Pontifical University of Chuquisaca. Domingo Savio Private University, Bolivia
+ Show More - Show Less
Corresponding Authors
Vladimir Camacho, Department of Morphophysiology, Universidad Mayor Real y Pontificia de San Francisco Xavier de Chuquisaca, Av. German Mendoza corner Mejillones, Sucre, Bolivia, Tel: 591-46422199; Email: camacho.vladimir@usfx.bo
Abstract

Neurotrophins are growth factors involved in the development and maintenance of the nervous system. The activation of these proteins involves the participation of oligosaccharides present in the surface cell membrane or in its receptors (Trk, p75NTR). This paper performs molecular modeling studies of available chemical databases in order to identify potential small-sugars that could serve as modulators of protein/receptor interactions. A library of 1043 compounds with high similarity to the chondroitin sulfate was downloading from PubChem library to be screened against neurotrophin-4/TrkB complex. Identification of small-sugars as allosteric modulators could control the interaction neurotrophin-receptor which is critically involved in angiogenesis process. A structural knowledge of the interactions of neurotrophin/small-sugars/TrkB complex will help to understand the biochemical pathways in which it is involved.

Keywords

Molecular modeling, Neurotrophins, Trk receptor, Virtual screening, Small-sugars

ABBREVIATIONS

NT: Neurotrophin; NGF: Nerve Growth Factor; BDNF: Brain-Derived Neurotrophic Factor; Trk: Tyrosine Receptor Kinase; p75NTR: p75 Neurotrophin Receptor; DD: Cell Death; CS: Chondroitin Sulfate; GAGs: Glycosaminoglycans; PDB: Protein Data Base; HTVS: High Throughput Virtual Screening; ADMETox: Absorption, Distribution, Metabolism, Excretion-Toxicity; PAINS: Pan Assay Interference Compounds

INTRODUCTION

Neurotrophin has been implicated in a great number of neurological disorders including Alzheimer and Parkinson’s disease [1]. The family of neurotrophins (NTs) is NGF, BDNF, NT-3, NT-4/5, NT-6 and NT-7 which have around 50% sequence homology [2]. Their activities are mediated by interacting with polysaccharides present on the surfaces of cell membranes or glycosylated receptors [3-6]. Those receptors are transmembrane proteins of two kinds; p75NTR receptor which can bond with all neurotrophins with low affinity and tyrosine receptor kinases (Trks) which are each specific for different neurotrophins (TrkA binds NGF, NT-7, TrkB binds BDNF, NT-3, NT-4/5, and TrkC is specific for NT-3) and have high affinity for those proteins [7,8]. NTs and Trks are highly preserved during evolution and have been detected in all vertebrate nervous systems and in some invertebrate so the origin of the NT/Trk signaling is prior to the origin of vertebrates. The simultaneous activation of Trks at the same time is a result of a wide range of cross-interactions between receptors and neurotrophins. 

The structural features of the Trk receptors consists of two cysteine cluster (C1, 2), three leucine-rich motif (Leu1, 2, 3), two immunoglobulin regions (IgC1, IgC-2) and one transmembrane domain to transduce signals which connects to the cytoplasmic region where a tyrosine kinase domain is present (Figure 1)

Figure 1 General structure of Neurotrophins (NGF, BDNF, NT-4 or NT-3) bond to the Trk/ p75NTR receptors. Sugars; GlcNAc, GalNAc.

Figure 1: General structure of Neurotrophins (NGF, BDNF, NT-4 or NT-3) bond to the Trk/ p75NTR receptors. Sugars; GlcNAc, GalNAc.

All Trk (TrkA, TrkB and TrkC) receptors are homologous in sequence (amino terminal forming the extracellular portion of the receptor where binding of the neurotrophin takes place). The p75NTR receptor has an extracellular region with cysteine rich regions (CR1-CR4), and one transmembrane domain which connects to the cytoplasmic domain involved in cell death (DD) [9]. The most common polysaccharides found in the extracellular matrix and on cell surfaces are oligosaccharides as heparin or chondroitin sulfate [4,5]. Interaction of neurotrophin with Trk receptors promotes neuron survival, whereas activation of p75NTR gives apoptosis and cell death [9]. Available crystal structures of Trk receptors and neurotrophins are a valuable resource for exploitation via molecular modeling its NT/Trk binding complex which will provide insight to structural regions that may be candidates for drug targeting and signaling pathway selection. NT/Trk interactions depend on many factors such as selectivity, binding affinity, and extracellular or intracellular modulation by other proteins.

In the literature has been described that anionic oligosaccharides as glycosaminoglycans (GAGs) are able to bind neurotrophic factors to form a large complex [10-13]. Chondroitin sulfate (CS) is a relevant family of glycosaminoglycan that participates in a large variety of biological events that are related to neural processes by regulating various GFs. It 

polysaccharide is composed of repeating 4)-β-GlcA-(1→3)-βGalNAc-)1→ disaccharide units. CS chains are modified by specific sulfotransferases with a sulfate group at C-2 of the glucuronic acid unit as well as C-4 and/or C-6 of the GalNAc residues, yielding various kinds of monosulfated or disulfated disaccharide units such as [GlcA-4OSGalNAc]n or [GlcA-6OSGalNAc]n or [GlcA-4,6OSGalNAc]n. Distinct modification patterns on CS are the structural basis for their biological functions and activities [14]. CSs have the ability to bind a large number of proteins, in particular to NTs. In the literature it is documented that CS binding site within the NT/Trk complex could be a potential mechanism for how CS promotes complex formation and modulates neurotrophin signaling [3]. Therefore, a structural knowledge of the interactions of neurotrophins with smallsaccharides will help to understand the biochemical pathways in which it is involved. Computational studies are the rational follow-up for structural analysis, as well as prior to functional analysis. So, crystal structure of the receptor and the growth factor is a valuable resource for docking molecular [15-18].

In this study, we have using molecular modeling of available chemical database to identify small-sugars that can be developed into novel neurotophins antagonist. NT-4/TrkB complex were used to perform the molecular modeling of 1043 sugars deposited in the PubChem library that share >80% similarity to the chemical structure of chondroitin sulfated disaccharide.

MATERIALS AND METHODS

he structure file from PDB ID 1hcf of the NT-4/TrkB complex was used to prepare the protein optimization [8] using the Protein Preparation Wizard module integrated within the Maestro suite software (Schrödinger, LLC, New York, NY, USA, 2019). Binding site was detecting using SiteMap from Schrödinger, LLC, New York, NY, 2021.

Chondroitin sulfate (CID 21873177) was used as lead structure to retrieve one library of 1043 compounds with structurally similar (Tanimoto similarity index >0.8) returned from an open chemistry database PubChem [19]. Low-energy 3D conformations of the compounds were retrieved using the Ligan Preparation module within the Maestro suite (Schrödinger, LLC, New York, NY, USA, 2019). Predict pKa values (neutral pH) were employed with the epik software and return all chemically sensible structures using Hammett and Taft methodology [20]. All small-sugars were minimized using the OPLS3e force field implemented in Maestro [21].

Molecular modeling was performed using High Throughput Virtual Screening (HTVS) Glide-dock module integrated in Maestro [22]. The docking grid was built around the amino acids Tyr96, Arg114, Gln94, Tyr329, and Asn350 with setting the dimensions of 20 Å to ensure a range that covered both proteins. Ligand poses generated in that manner were run through a series of hierarchical filters to evaluate ligand interactions with the protein. Upon conformational analyses and structure optimization, the structures contained within each library were analyzed via HTVS using Glide docking as implemented in the Maestro software. Docking glide scores, specific interactions with amino acid in the interface pocket and structural diversity were considered for selecting the most promising ligands. The ADME/Tox parameters were calculated using QikPro integrated in Schrödinger. After that, PAINS (pan-assay interference compounds) identification was obtained using swiss ADME webserver [23] to filter-off molecules containing such chemical groups Scheme 1.

Scheme 1 Workflow for the identification of novel Neutrophin inhibitors

Scheme 1: Workflow for the identification of novel Neutrophin inhibitors

RESULTS AND DISCUSSION

Neurotrophin/Trk complex as a suitable drug target

Neurotrophins (NTs) are a family of homologous proteins synthesized as precursors in a pro-form and secreted in form of mature protein dimers. Only upon dimerization is there a hydrophobic core to stabilize the structure of the growth factor. The binding of neurotrophin to their respective Trk initiates intracellular signals essential for the growth and survival of neurons. Several crystal structures of NTs and neurotrophin/ receptor complexes are deposited in the Protein data Base (PDB) (Table 1).

Table 1: Neurotrophins and neurotrophin/receptor complex deposited in the PDB.

Neurotrophin Receptor PDB Chain Organism Reference
DNF/NT-4 ---- 1b8m A, B H. sapiens [24]
NT-4 ---- 1b8k, 1b98 A, B H. sapiens [24]
BDNF/NT-3 ---- 1bnd A,B H. sapiens [25]
NGF - ---- 1bet A,B Mus muculus [26]
NGF TrkB 1www A,B H. sapiens [26]
NT-4 TrkB 1hcf A,B,X H. sapiens [8]
NGF TrkA/p75 2ifj A-P H. sapiens [7]
BDNF/NGF ----- 1nt3 A,B H. sapiens [2]
NGF TrkA 1he7 A,B H. sapiens [8]

proteins (Ser21, Ala19, Cys119, Lys93, Gln94, His299 and Asn350).

3D-structure of neurotrophin/receptor complex reveals common features that may be important in the binding between the neurotrophins with oligosaccharides which would initiate intracellular signals essential for the growth and survival of neurons.

The overall structure of NT’s dimmer interface (homodimer or heterodimer) presents similar patterns of nonpolar contact and hydrogen bonds. The structure of neurotrophin-4 bound to Ig-C2TrkB receptor is showed in Figure 2.

The most commonoligosaccharide ligands for neurothrophins are glycosaminoglicans (Hepara and chondroitin sulfates). So, that process could be control by new small sugars with similarity structural to those oligosaccharides. So, novel small-sugars able to recognize neurotrophins with high affinity could avoid the formation of the NT/Trk complex. In order to identify novel small-sugars as allosteric modulators of neurotrophin/receptor complex a chemical library of compounds that are structurally related to glycosaminoglicans as chondroitin sulfate was carefully screened and analyzed.

According to the molecular simulation of a ternary structure of the NT/TrkB complex, we determined the amino acid residues that participate in the physical interaction between these two proteins [21]. The identification of binding site of NT-4/TrkB complex was carried out using SiteMap tool from Schrodinger (Figure 2)

Figure 2 3-D Structure of NT-4 (blue) /Ig-C2TrkB (grey) complex [24] (PDB ID 1hcf).

Figure 2: 3-D Structure of NT-4 (blue) /Ig-C2TrkB (grey) complex [24] (PDB ID 1hcf).

 The interface site was employed to define the active site for High Throughput Virtual Screening (HTVS) experiments. A chemical database of compounds sharing >0.8 Tanimoto similarity index with chondroitin sulfate and complying Lipinski’s rules was retrieved from PubChem. This library of 1043 small-sugars was used as the input source for our HTVS upon ligand preparation using the OPLS3 force field. This library of sugars was then subjected to molecular docking studies using the HTVS glide dock module from Schrodinger [19,20]. High precision docking calculations using XP were accomplished for the compounds with the highest docking scores in the HTVS. Hit compound (21873177) and selected candidates based in specific interactions, structural diversity and docking glide scores are shown in Figure 3.
 

Figure 3 2D structure of chondroitin sulfate (hit compound, 21873177) and novel small-sugars as modulators of neurotrophin/ TrkB interactions.

Figure 3: 2D structure of chondroitin sulfate (hit compound, 21873177) and novel small-sugars as modulators of neurotrophin/ TrkB interactions.

Dock of the lead compound within the NT-4/TrkB complex showed structural details of the interactions between neurotrophin-4/receptor complex and chondroitin sulfate (Figure 4)

Figure 4 NT-4(blue)/TrkB(grey) in complex with the lead compound (21873177 stick representation in purple). Interactions are shown in dashed lines; H-bond (yellow); salt bridge (pink).Docking score -9.63 kcal/mol.

Figure 4: NT-4(blue)/TrkB(grey) in complex with the lead compound (21873177 stick representation in purple). Interactions are shown in dashed lines; H-bond (yellow); salt bridge (pink).Docking score -9.63 kcal/mol.

(-9.6 kcal/mol docking score). The disaccharide is place in the interface site of both proteins, establishing seven H-bonding and one salt bridge with different residues of both

In Figure 5

Figure 5 (A) Ligand interaction of 140843825 with NT/TrkB complex; (B) dock of chondroitin sulfate (grey) and 140843825 (green) in the binding site of complex.

Figure 5: (A) Ligand interaction of 140843825 with NT/TrkB complex; (B) dock of chondroitin sulfate (grey) and 140843825 (green) in the binding site of complex.

are represented ligand interaction diagrams and dock of one of the best disacharide retrieved from the chemical library (ID 140843825). The novel sugar demostrate that the sulfate part of chondrotin in the GalNAc residue can be substituted by a simple hydroxyl group (-11.33 kcal/mol) or can be present in the GlcA residue (ID 133587484) improving the number of stabilizing interactions with NT-4/TrkB complex.

Ligands 132011282 and 129268038 where hydroxyl groups have been substituted by methyl groups keep the crucial interactions with the protein-receptor complex and even improve the predicted energy of complex formation (Table 2).

Compound  QPlog QPlogHERG QPPCaco QPlogBB HOA(%) Docking score
46836188 -0.82 -0.67 0.62 -3.38 0 -12.49
129268038  -0.23 -0.75 1.15 -3.06 0 -11.29
118118706  -0.31 -0.77 2.21 -2.76  0 -10.88
68320140  -0.36 -0.54 1.86 2.70 0 -10.77
133587484  -0.35 1.28 0.12 -3.33 0 -10.60
5159033  0.45 0.66 0.007 -5.29 0 -10.51
59679785  -0.14 -0.36 2.86 -2.54  0 -10.43
132011282  -0.97 -1.2 7.41 -2.23 33.79 -10.34
68320140  -0.38 -0.56 1.43 -2.82 0 -10.27
68355982  -0.48 -0.7 13.86 -1.89 22.06 -10.03
21873177  -0.18 0.89 0.016 -4.46 0 -9.63
57572422  -0.20 -0.53 4.88 -2.41 0 -9.56
59503940  -1.43 -0.96 2.53 -2.69 0 -8.54
142592620  -0.15 -1.9 43.37 -1.64 41.24 -8.42
156351981  0.49 -1.5 0.071 -4-40 0 -7.5
QPlog, predicted aqueous solubility [-6.5/0.5]; QPlogHERG K+ Channel Blockage (log IC50) [concern below -5]; Apparent QPPCaco-2 cell permeability in nm/s [500 excellent]; QPlogBB, predicted log of the brain/blood partition coefficient [-3.0/1.2]; Human Oral Absorption in GI [<25% is poor]. PAINS were 0 for all compounds

The new small-sugars should present a strong interaction pattern and docking scores but also a predicted good druggability profile when compared to their reference compound (Table 2). Fourteen compounds were identified as the most promising drug candidates. The most remarkable small sugars from this library are 132011282 and 142592620 (monosaccharide), which showed good interaction energy (six or five H-bonds 

with docking score -10.34 or -8.42kcal/mol respectively) and a predicted better absorption and cell permeability than lead compound (Table 2, line green).

CONCLUSION

Today, most available NT modulators have a very high molecular weight along with an unfavorable pharmacogenability profile (oligosaccharides such as chondroitin sulfate or heparin sulfate). In silico methods allow much larger targets to be explored than can be accessed experimentally, and can be used to design new ligands. Our computational modeling studies have identified better novel small sugars with optimal drug-like characteristics. In the clinical field it is known that the use of neurotrophins is very limited due to the large number of signals induced by these neurotrophic factors, however, and thanks to the identification of allosteric modulators of the NT-4/TrkB complex, it is concluded that they could be have favorable implications in the treatment of neurodegenerative diseases such as Parkinson’s, Alzheimer’s, amyotrophic sclerosis and others where a dysregulation and decrease of neurotrophins that prevent the development, maintenance and survival of neurons in the central nervous system has been demonstrated.

ACKNOWLEDGEMENTS

To Dr. Aghata Bastida for her academic and professional support in the preparation of this article, Institute of General Organic Chemistry, Department of Bio-organic Chemistry, Spanish National Research Council (CSIC), Madrid Spain. To 

Dr. Sandra Zárate Segóvia, for her support in the elaboration, revision and comments of this work, Chemical Engineering Career, Universidad Mayor Real and Pontificia San Francisco Xavier de Chuquisaca, Sucre-Bolivia.

REFERENCES

1. Xu-Qiao Chen, Mariko Sawa, William C Mobley. Dysregulation of neurotrophin signaling in the pathogenesis of Alzheimer disease and of Alzheimer disease in Down syndrome. Free Radic Biol Med. 2018; 114: 52–61.

2. M J Butte, PK Hwang, WC Mobley, RJ Fletterick. Crystal structure of neurotrophin-3 homodimer shows distinct regions are used to bind its receptors. Biochemistry. 1998; 37: 16846–16852.

3. R Claude J Rogers, Peter M Clark, Sarah E Tully, Ravinder Abrol, K Christopher Garcia, William A Goddard 3rd, et al. Elucidating glycosaminoglycan - protein - protein interactions using carbohydrate microarray and computational approaches. Proc Natl Acad Sci U S A. 2011; 108: 9747–9752.

4. Kurihara D, Yamashita T. Chondroitin sulfate proteoglycans down-regulate spine formation in cortical neurons by targeting tropomyosin-related kinase B (TrkB) protein. J Biol Chem. 2012; 287: 13822–13828.

5. Sanaullah Khan, Jayesh Gor, Barbara Mulloy, Stephen J Perkins. SemiRigid Solution Structures of Heparin by Constrained X-ray Scattering Modelling: New Insight into Heparin-Protein Complexes. J Mol Biol. 2010; 395: 504–521.

6. C RD Cummings, AM Soderquist, G Carpenter. The oligosaccharide moieties of the epidermal growth factor receptor in A-431 cells. Presence of complex-type N-linked chains that contain terminal N-acetylgalactosamine residues. J Biol Chem. 1985; 260: 11944– 11952

7. W Tom Wehrman, Xiaolin He, Bill Raab, Abhiram Dukipatti, Helen Blau, K Christopher Garcia. Structural and Mechanistic Insights into Nerve Growth Factor Interactions with the TrkA and p75 Receptors. Neuron. 2007; 53: 25–38

8. MJ Banfield, RL Naylor, AG Robertson, SJ Allen, D Dawbarn, RL Brady. Specificity in Trk receptor:neurotrophin interactions: The crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Structure. 2001; 9: 1191–1199.

9. Bibel M, Barde YA. Neurotrophins: Key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev. 2000; 14: 2919– 2937.

10. Raúl Benito-Arenas, Ernesto Doncel-Pérez, Mar Fernández-Gutiérrez, Leoncio Garrido, Eduardo García-Junceda, Julia Revuelta, et al. A holistic approach to unravelling chondroitin sulfation: Correlations between surface charge, structure and binding to growth factors. Carbohydr Polym. 2018; 202: 211–218.

11.Kanato Y, Ono S, Kitajima K, Sato C. Complex formation of a brainderived neurotrophic factor and glycosaminoglycans. Biosci Biotechnol Biochem. 2009; 73: 2735–2741.

12. Gregory M Miller, Linda C Hsieh-Wilson. Sugar-dependent modulation of neuronal development, regeneration, and plasticity by chondroitin sulfate proteoglycans. Exp Neurol. 2015; 274: 115–125.

13.L Djerbal, H Lortat-Jacob, Jcf Kwok. Chondroitin sulfates and their binding molecules in the central nervous system. Glycoconj J. 2017; 34: 363–376.

14.Giulia Vessella, José Antonio Vázquez, Jesús Valcárcel, Laura Lagartera, Dianélis T Monterrey, Agatha Bastida, et al. Deciphering Structural Determinants in Chondroitin Sulfate Binding to FGF-2: Paving the Way to Enhanced Predictability of their Biological Functions. Polymers (Basel). 2021; 13: 313.

15.Sima Beigoli, Atena Sharifi Rad, Azam Askari, Reza Assaran Darban, Jamshidkhan Chamani. Isothermal titration calorimetry and stopped flow circular dichroism investigations of the interaction between lomefloxacin and human serum albumin in the presence of amino acids. Journal of Biomolecular Structure and Dynamics. 2019; 37: 2265-2282.

16.Khashkhashi-Moghadam, S Ezazi-Toroghi, S Kamkar-Vatanparast, M Jouyaeian, P Mokaberi, P Yazdyani, et al. Novel perspective into the interaction behavior study of the cyanidin with human serum albumin-holo transferrin complex: Spectroscopic, calorimetric and molecular modeling approaches. Journal of Molecular Liquids. 2022; 356: 119042.

17.Narges Marjani, Maryam Dareini, Maryam Asadzade-Lotfabad, Mahtab Pejhan, Parisa Mokaberi, Zeinab Amiri-Tehranizadeh, et al. Evaluation of the binding effect and cytotoxicity assay of 2-Ethyl-5- (4-methylphenyl) pyramido pyrazole ophthalazine trione on calf thymus DNA: spectroscopic, calorimetric, and molecular dynamics approaches. Luminescence. 2022; 37: 310-322.

18.Dareini M, Amiri Tehranizadeh Z, Marjani N, Taheri R, AslaniFiroozabadi S, Talebi A, et al. A novel view of the separate and simultaneous binding effects of docetaxel and anastrozole with calf thymus DNA: Experimental and in silico approaches. Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy. 2020; 228: 117528.

19.Sunghwan Kim, Jie Chen, Tiejun Cheng, Asta Gindulyte, Jia He, Siqian He, et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res. 2021; 49: D1388–D1395.

20.Jeremy R Greenwood, David Calkins, Arron P Sullivan, John C Shelley. Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution. J Comput Aided Mol Des. 2010; 24: 591–604.

21.Edward Harder, Wolfgang Damm, Jon Maple, Chuanjie Wu, Mark Reboul, Jin Yu Xiang, et al. OPLS3?: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. 2016; 12: 281- 96.

22.Warren GL, Andrews CW, Capelli AM, Clarke B, LaLonde J, Lambert MH, et al. A critical assessment of docking programs and scoring functions. J Med Chem. 2006; 49: 5912–5931.

23.Antoine Daina, Olivier Michielin, Vincent Zoete. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7: 42717.

24.RC Robinson, C Radziejewski, G Spraggon, J Greenwald, MR Kostura, LD Burtnick, et al. The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci. 1999; 8: 2589–2597.

25.Robinson RC, Radziejewski C, Stuart DI, Jones EY. April 4, 1995 Accelerated Publications. 1995; 34: 4139–4146. 

26.Wlesmann C. Ultsch M.H. Bass S.H. De Vos A.M. Crystal structure of nerve growth factor in complex with the ligand- binding domain of the TrkA receptor. Nature. 1999; 401: 184–188.

Camacho V, Bastida A, Zárate SG (2022) Identification of Small-Sugars as Modulators of Neurotrophin-Receptor Interactions. JSM Chem 9(1): 1057

Received : 21 Apr 2022
Accepted : 25 May 2022
Published : 28 May 2022
Journals
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X