Insight into the molecular interaction between the anticancer drug, enzalutamide and human alpha-2-macroglobulin: Biochemical and biophysical approach.

The drug pharmacokinetics is affected upon binding with proteins, thus making drug-protein interactions crucial. This study investigated the interaction between enzalutamide and human major antiproteinase alpha-2-macroglobulin (α2M) by using multi spectroscopic and calorimetric techniques. The spectroscopic techniques such as circular dichroism (CD), intrinsic fluorescence, and UV-visible absorption were used to determine the mechanism of enzalutamide-α2M interaction. Studies on the quenching of fluorescence at three different temperatures showed that the enzalutamide-α2M complex is formed through static quenching mechanism. The change in microenvironment around tyrosine residues in protein was detected through synchronised fluorescence. The secondary structure of α2M was slightly altered by enzalutamide according to far UV-CD spectral analysis. Changes in position of amide I band in FTIR spectra further confirm the secondary structural alteration in α2M. According to thermodynamic characteristics such as fluorescence quenching and isothermal titration calorimetry (ITC), hydrogen bonds and hydrophobic interactions were involved in the interaction machanism. The ITC reiterated the exothermic and spontaneous nature of the interaction. The lower proteinase inhibitory activity of the α2M-enzalutamide conjugate as reflects the disruption of the native α2M structure upon interaction with enzalutamide.

Binding characteristics and conformational changes in alpha-2-macroglobulin by the dietary flavanone naringenin: biophysical and computational approach.

In the present study, we investigated the interaction of alpha-2-macroglobulin (α2M) with naringenin using multi-spectroscopic, molecular docking, and molecular simulation approaches to identify the functional changes and structural variations in the α2M structure. Our study suggests that naringenin compromised α2M anti-proteinase activity. The results of absorption spectroscopy and fluorescence measurement showed that naringenin-α2M formed a complex with a binding constant of (kb)∼104, indicative of moderate binding. The value of ΔG° in the binding indicates the process to be spontaneous and the major force responsible to be hydrophobic interaction. The findings of FRET reveal the binding distance between naringenin and the amino acids of α2M was 2.82 nm. The secondary structural analysis of α2M with naringenin using multi-spectroscopic methods like synchronous fluorescence, red-edge excitation shift (REES), FTIR, and CD spectra further confirmed the significant conformational alterations in the protein. Molecular docking approach reveals the interactions between naringenin and α2M to be hydrogen bonds, van der Waals forces, and pi interactions, which considerably favour and stabilise the binding. Molecular dynamics modelling simulations also supported the steady binding with the least RMSD deviations. Our study suggests that naringenin interacts with α2M to alter its confirmation and compromise its activity.Communicated by Ramaswamy H. Sarma.

Probing the binding of morin with alpha-2-macroglobulin using multi-spectroscopic and molecular docking approach : Interaction of morin with α2M.

Alpha-2-macroglobulin (α2M) is an essential antiproteinase that is widely distributed in human plasma. The present study was aimed at investigating the binding of a potential therapeutic dietary flavonol, morin, with human α2M using a multi-spectroscopic and molecular docking approach. Recently, flavonoid-protein interaction has gained significant attention, because a majority of dietary bioactive components interact with proteins, thereby altering their structure and function. The results of the activity assay exhibited a 48% reduction in the antiproteolytic potential of α2M upon interaction with morin. Fluorescence quenching tests unequivocally confirmed quenching in the fluorescence of α2M in the presence of morin, conforming complex formation and demonstrating that the binding mechanism involves a dynamic mode of interaction. Synchronous fluorescence spectra of α2M with morin showed perturbation in the microenvironment around tryptophan residues. Furthermore, structural changes were observed through CD and FT-IR, showing alterations in the secondary structure of α2M induced by morin. FRET further supports the results of the dynamic mode of quenching. Moderate interaction is shown by binding constant values using Stern-Volmer's fluorescence spectroscopy. Morin binds to α2M at 298 K with a binding constant of 2.7 × 104 M-1, indicating the strength of the association. The α2M-morin system was found to have negative ΔG values, which suggests that the binding process was spontaneous. Molecular docking also reveals the different amino acid residues involved in this binding process, revealing that the binding energy is -8.1 kcal/mol.

Exploring the interaction of myricetin with human alpha-2-macroglobulin: biophysical and in-silico analysis.

Myricetin (MYR) is a bioactive secondary metabolite found in plants that is recognized for its nutraceutical value and is an essential constituent of various foods and beverages. It is reported to exhibit a plethora of activities, including antioxidant, antimicrobial, antidiabetic, anticancer, and anti-inflammatory. Alpha-2-macroglobulin (α2M) is a major plasma anti-proteinase that can inhibit proteinases of both human and non-human origin, regardless of their specificity and catalytic mechanism. Here, we explored the interaction of MYR-α2M using various biochemical and biophysical techniques. It was found that the interaction of MYR brings subtle change in its anti-proteolytic potential and thereby alters its structure and function, as can be seen from absorbance and fluorescence spectroscopy. UV spectroscopy of α2M in presence of MYR indicated the occurrence of hyperchromism, suggesting complex formation. Fluorescence spectroscopy reveals that MYR reduces the fluorescence intensity of native α2M with a shift in the wavelength maxima. At 318.15 K, MYR binds to α2M with a binding constant of 2.4 × 103 M-1, which indicates significant binding. The ΔG value was found to be - 7.56 kcal mol-1 at 298.15 K, suggesting the interaction to be spontaneous and thermodynamically favorable. The secondary structure of α2M does not involve any major change as was confirmed by CD analysis. The molecular docking indicates that Asp-146, Ser-172, Glu-174, and Tyr-180 were the key residues involved in α2M-MYR complex formation. This study contributes to our understanding of the function and mechanism of protein and flavonoid binding by providing a molecular basis of the interaction between MYR and α2M.

Comprehensive insight into the molecular interaction of an anticancer drug-ifosfamide with human alpha-2-macroglobulin: biophysical and in silico studies.

Ifosfamide is an active alkylating chemotherapeutic drug chemically related to nitrogen mustard. The pharmacokinetics of drugs is affected upon binding with protein, making the studies on drug-protein interaction promising. The present study investigates the interaction between ifosfamide and human antiproteinase-alpha-2-macroglobulin (α2M) by using multi-spectroscopic and in silico techniques. The UV-visible absorption, intrinsic fluorescence and circular dichroism (CD) spectroscopic methods were employed to unveil the mode and mechanism of ifosfamide-α2M interaction. Fluorescence quenching studies performed at three different temperatures indicated that ifosfamide-α2M complex formation involves static quenching. Far UV-CD spectra revealed a minor alteration in the secondary structure of α2M instigated by ifosfamide. The thermodynamic parameters determined by fluorescence quenching experiment and isothermal titration calorimetry (ITC) suggested that the complex between ifosfamide and α2M involves hydrogen bonding and hydrophobic interactions. Molecular docking illustrates that ifosfamide binds with moderate affinity to Lys1240, Asn173, Ser957, Leu955, Asp953, Lys1216 and Thr1236 residues during the interaction. Molecular dynamic (MD) simulation suggested that the ifosfamide forms a stable complex with α2M. Communicated by Ramaswamy H. Sarma.

Characterization of the binding between anti-tumor drug 5-fluorouracil and human alpha-2-macroglobulin: spectroscopic and molecular docking analyses.

5-Fluorouracil (5-FU) is a well-recognized anticancer drug used in the treatment of tumors of head, neck and breast. Drug pharmacokinetics is affected upon binding with protein, thus, making drug-protein interactions imperative to study. Present work investigates the interaction between 5-FU and human major antiproteinase-alpha-2-macroglobulin (α2M) by multi-spectroscopic, calorimetric and molecular docking techniques. UV/Visible absorption, intrinsic fluorescence and circular dichroism (CD) spectroscopic methods have been employed to unveil the mode and mechanism of 5-FU-α2M interaction. Synchronous fluorescence showed alteration in the microenvironment of tryptophan and tyrosine residues of protein. Far UV-CD spectra suggest slight alterations in the secondary structure of α2M by 5-FU. Thermodynamic parameters determined by fluorescence quenching experiments and isothermal titration calorimetry (ITC) suggested the involvement of hydrogen bonds and hydrophobic interactions. Moreover, ITC corroborate the spontaneous and exothermic nature of the interaction process. Molecular docking illustrates that 5-FU binds with moderate affinity and Asp953, Tyr1264, Lys1236, Thr1232, Tyr1323 and Leu951 were the main residues involved. Molecular dynamics simulation studies suggested that 5-FU was stabilizing the α2M structure and forming a stable complex. It was concluded that 5-FU lower the antiproteolytic activity of α2M significantly and causes disruption in the native structure and conformation of α2M.Communicated by Ramaswamy H. Sarma.

Interaction of Human Alpha-2-Macroglobulin with Pesticide Aldicarb Using Spectroscopy and Molecular Docking.

BACKGROUND: Aldicarb is a carbamate pesticide commercially used in potato crop production. Once it enters human body, it interacts with diverse proteins and other substances. OBJECTIVE: Aldicarb is toxic to human health and it is also a cholinesterase inhibitor, which prevents the breakdown of acetylcholine in synapse. Human alpha-2-macroglobulin (α2M), is a large tetrameric glycoprotein of 720 kDa with antiproteinase activity, found abundantly in plasma. METHODS: In the present study, the interaction of aldicarb with alpha-2-macroglobulin was explored utilizing various spectroscopic techniques and molecular docking studies. RESULTS: UV-vis and fluorescence spectroscopy suggests the formation of a complex between aldicarb and α2M apparent by increased absorbance and decreased fluorescence with static quenching mode. CD spectroscopy indicates a slight change in the structure of alpha-2-macroglobulin. Docking studies confirm the interaction of aldicarb with Pro- 1391, Leu-1392, Lys-1393, Val-1396, Lys- 1397, Thr-1408, Glu-1409, Val-1410, Asp-282 and Glu-281 in the receptor binding domain at the C-terminal of the alpha 2 macroglobulin. DISCUSSION: In this work, aldicarb is shown to bind with alpha 2-macroglobulin at receptor binding domain which is the binding site for various extracellular and intracellular ligand too. Also, affecting the functional activity of the protein may lead to further physiological consequences. CONCLUSION: It is possible that aldicarb binds and compromises antiproteinase activity of α2M and binding properties by inducing changes in the secondary structure of the protein.

SWIR emissive RosIndolizine dyes with nanoencapsulation in water soluble dendrimers.

Shortwave infrared (SWIR) emission has great potential for deep-tissue in vivo biological imaging with high resolution. In this article, the synthesis and characterization of two new xanthene-based RosIndolizine dyes coded PhRosIndz and tolRosIndz is presented. The dyes are characterized via femtosecond transient absorption spectroscopy as well as steady-state absorption and emission spectroscopies. The emission of these dyes is shown in the SWIR region with peak emission at 1097 nm. TolRosIndz was encapsulated with an amphiphilic linear dendritic block co-polymer (LDBC) coded 10-PhPCL-G3 with high uptake yield. Further, cellular toxicity was examined in vitro using HEK (human embryonic kidney) cells where a >90% cell viability was observed at practical concentrations of the encapsulated dye which indicates low toxicity and reasonable biocompatibility.

Interaction of organophosphate pesticide chlorpyrifos with alpha-2-macroglobulin: Biophysical and molecular docking approach.

Organophosphate class of pesticides causes neurotoxicity and carcinogenicity in humans. Once inside the human body, these pesticides often interact with plasma proteins, such as alpha-2-macroglobulin (α2M) which is the key anti-proteinase. Our work focuses on the structural and functional alteration of α2M by chlorpyrifos (CPF), a member of organophosphates. We explored the binding interaction between alpha-2-macroglobulin and CPF by using UV absorption and fluorescence spectroscopy (steady state and synchronous), circular dichroism and molecular docking approach. The functional activity of α2M was analyzed by anti-proteinase trypsin inhibitory assay which showed dose-dependent decrease in alpha-2-macroglobulin antiproteolytic potential. UV absorption studies and fluorescence quenching experiments suggested the formation of a complex between α2M and CPF. The CD spectra suggested a reduction in the beta helical (ß helix) content of α2M. Analysis of thermodynamic parameters suggested the process is spontaneous and endothermic with the ΔG and ΔH values being -5.501 kJ/mol, 11.49 kJ/mol, respectively. CPF binds with Ile-1390, Pro-1391, Leu-1392, Lys-1393, Val-1396, Lys-1397, Arg-1407, Thr-1408, Glu-1409, Val-1410, Asp-282, Glu-281 of α2M as suggested by molecular docking.

Bilirubin binding affects the structure and function of alpha-2-macroglobulin.

Bilirubin is an endogenous antioxidant that is a metabolite of the heme in red blood cells (RBC). In blood, bilirubin is associated with albumin to form a water-soluble complex, known as unconjugated bilirubin. Alpha-2-macroglobulin (α2M) is a proteinase inhibitor found in the plasma of vertebrates. In the present study, we have investigated the interaction of photo-illuminated bilirubin with serum α2M using various biophysical and thermodynamic techniques. The binding of bilirubin to α2M leads to various functional and structural changes in α2M protein. The result of ultraviolet (UV) and fluorescence spectroscopy suggests that binding of bilirubin to α2M induces a conformational change in the secondary structure of protein which was corroborated by circular dichroism (CD) and Fourier-transform infrared spectroscopy (FT-IR). This binding leads to the conversion of ß-sheet into α-helical conformation and subsequently loss in protein activity. The thermodynamic parameters of bilirubin-α2M binding indicate that the binding is exothermic, and the reaction spontaneous. Our studies show that binding of bilirubin with α2M in the presence of light induces structural and functional modifications in the protein. Bilirubin possesses multiple biological activities, including immunomodulatory property which has not been extensively explored and which may be of interest for further study.

Moving in for Renovations: An Innovative Solution for Replacing End-of-Life Capital Equipment. The Michael Garron Hospital-Sunnybrook Collaborative Catheterization Laboratory Project.

Replacement of an end-of-life cardiac catheterization laboratory ("cath lab") can pose a significant challenge to a hospital, particularly in single-cath-lab institutions. The disruption in patient care requires innovative approaches to minimize the inconvenience and ensure ongoing quality of care. We describe a unique approach whereby Michael Garron Hospital (MGH) "leased" a cath lab within Sunnybrook Health Sciences Centre for a 12-week period during a cath lab replacement project at MGH. The MGH cath lab and patient recovery bay remained a completely separate entity staffed by MGH nurses and physicians, with electronic connection to the home hospital. A total of 420 patients underwent cardiac catheterization with no adverse outcomes while maintaining system efficiency and high patient and staff satisfaction. Cath lab leasing involving two cooperating hospitals is an innovative and safe way to bridge a cath lab replacement.

Understanding oxidants and antioxidants: Classical team with new players.

The free radical oxidants such as reactive oxygen species, reactive nitrogen species, and reactive sulfur species are produced inside cells through various metabolic processes. The body is equipped with an antioxidant defense system that guards against oxidative damage caused by these reactive oxidants and plays a major role in protecting cells from oxidative stress and damage. Antioxidants such as glutathione (GSH), thioredoxin, ascorbic acid and enzymes, for example, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) counter the oxidative stress and protect lipids, proteins, and DNA. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids are also natural antioxidants present in foods. There is increasing demand and availability of designer foods fortified with antioxidants and probiotics that may be important in human health. The review article presents a brief overview of oxidants and antioxidant systems inside the human body including the role of probiotics and inflammation. PRACTICAL APPLICATIONS: Antioxidants such as GSH, thioredoxin, ascorbic acid, etc. and protective enzymes, for example, SOD, GPx, CAT, etc. counter oxidative stress and protect cellular biomolecules. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids, phospholipids, and sterols are natural antioxidants found in consumed foods. They play a major role in scavenging free radical and non-radical oxidants, and protect cells from oxidative stress and damage. The importance of antioxidants can be understood from the fact that oxidative damage is now associated with a variety of diseases including cancer, neurodegeneration, diabetes, etc. Several approaches to improve human health and achieve longevity use dietary antioxidants as formulation in diet and fortified foods. Antioxidants also maintain freshness and prolonging the shelf life of food products. The fortified or designer foods that are added with antioxidant nutrients and the use of microorganisms as probiotics are increasingly available in the market as health foods and supplements.

Self-Assembling PCL-PAMAM Linear Dendritic Block Copolymers (LDBCs) for Bioimaging and Phototherapeutic Applications.

This study represents a successful approach toward employing polycaprolactone-polyamidoamine (PCL-PAMAM) linear dendritic block copolymer (LDBC) nanoparticles as small-molecule carriers in NIR imaging and photothermal therapy. A feasible and robust synthetic strategy was used to synthesize a library of amphiphilic LDBCs with well-controlled hydrophobic-to-hydrophilic weight ratios. Systems with a hydrophobic weight ratio higher than 70% formed nanoparticles in aqueous media, which show hydrodynamic diameters of 51.6 and 96.4 nm. These nanoparticles exhibited loading efficiencies up to 21% for a hydrophobic molecule and 64% for a hydrophilic molecule. Furthermore, successful cellular uptake was observed via trafficking into endosomal and lysosomal compartments with an encapsulated NIR theranostic agent (C3) without inducing cell death. A preliminary photothermal assessment resulted in cell death after treating the cells with encapsulated C3 and exposing them to NIR light. The results of this work confirm the potential of these polymeric materials as promising candidates in theranostic nanomedicine.

Quercetin-induced inactivation and conformational alterations of alpha-2-macroglobulin: multi-spectroscopic and calorimetric study.

Quercetin is a widely used bioflavonoid found in onions, grapes, berries and citrus fruits. Under certain conditions, quercetin acts as a pro-oxidant thereby generating reactive oxygen species and promoting the oxidation of molecules. Our study investigates the effect of quercetin on the structure and function of alpha-2-macroglobulin (α2M) by employing various biophysical techniques and trypsin inhibitory assay. α2M is the major antiproteinase present in the plasma of vertebrates. Results of activity assay indicated that α2M loses its 56% of inhibitory activity on treatment with quercetin in the presence of light. UV spectroscopy reveals hyper chromaticity in absorption spectra of protein on interaction with quercetin suggesting structural change. The intrinsic fluorescence studies showed quenching of α2M spectra in the presence of quercetin, and the mode of quenching was found to be static in nature. Synchronous fluorescence indicated the alteration in the microenvironment of tryptophan residues. CD and FTIR spectroscopy confirms concentration-dependent alterations in secondary structure of α2M instigated by quercetin. The magnitude of binding constant, enthalpy change, entropy change and free energy change during the interaction process was determined by isothermal titration calorimetry. Hydrogen bonding and hydrophobic interaction were the main intermolecular forces involved during the process. This study identifies and signifies the damage induced by quercetin to α2M due to its pro-oxidant action. Communicated by Ramaswamy H. Sarma.

Influence of Ascorbic Acid on the Structure and Function of Alpha-2- macroglobulin: Investigations using Spectroscopic and Thermodynamic Techniques.

BACKGROUND: Ascorbic acid is a classic dietary antioxidant which plays an important role in the body of human beings. It is commonly found in various foods as well as taken as dietary supplement. OBJECTIVE: The plasma ascorbic acid concentration may range from low, as in chronic or acute oxidative stress to high if delivered intravenously during cancer treatment. Sheep alpha-2- macroglobulin (α2M), a human α2M homologue is a large tetrameric glycoprotein of 630 kDa with antiproteinase activity, found in sheep's blood. METHODS: In the present study, the interaction of ascorbic acid with alpha-2-macroglobulin was explored in the presence of visible light by utilizing various spectroscopic techniques and isothermal titration calorimetry (ITC). RESULTS: UV-vis and fluorescence spectroscopy suggests the formation of a complex between ascorbic acid and α2M apparent by increased absorbance and decreased fluorescence. Secondary structural changes in the α2M were investigated by CD and FT-IR spectroscopy. Our findings suggest the induction of subtle conformational changes in α2M induced by ascorbic acid. Thermodynamics signatures of ascorbic acid and α2M interaction indicate that the binding is an enthalpy-driven process. CONCLUSION: It is possible that ascorbic acid binds and compromises antiproteinase activity of α2M by inducing changes in the secondary structure of the protein.

Understanding the binding interaction between methotrexate and human alpha-2-macroglobulin: Multi-spectroscopic and computational investigation.

Methotrexate (MTX) is advised in the treatment of solid tumours, hematologic malignancies and autoimmune disorders. On reaching the circulation, 60% of MTX is bound to the proteins present in serum. Alpha-2-macroglobulin (α2M) is a plasma proteinase inhibitor with numerous functions such as binding, transportation and targeting of molecules. Our studies are the first attempt to investigate the binding interaction of pharmacologically important drug MTX, and highly abundant proteinase inhibitor- α2M. The protein functional activity assay shows 53% decrease in antiproteolytic potential of α2M upon drug interaction. The binding of MTX with α2M was studied by various biophysical methods. UV-visible absorption spectroscopy reveals hyperchromicity of α2M spectra upon drug binding. The intrinsic fluorescence spectra show quenching in fluorescence intensity of α2M and the mechanism of quenching was found to be static in nature. Far UV-CD spectra unveil slight alteration in secondary structure of α2M upon drug binding. Isothermal titration calorimetry (ITC) reveals the value of thermodynamic parameters and which affirms the binding process to be spontaneous and exothermic. Molecular docking illustrates that Asn173, Leu1298, Gly172, Lys1240, Gln1325, Ser1327, Glu913, Asn1139, Lys1236, Leu951 and Arg1297 were the key residues involved during interaction process. Molecular dynamics (MD) simulation studies suggest that MTX form a stable complex with α2M. Our study assumes importance from the fact that MTX is known to bind plasma proteins quite efficiently.

Inactivation of Alpha-2-Macroglobulin by Photo-Illuminated Gallic Acid.

Gallic acid is a naturally occurring plant polyphenol found in green tea and various fruits. Under certain conditions gallic acid exhibits pro-oxidant characteristics rather than its well known antioxidant property. In the present work, we explored the interaction of gallic acid with sheep alpha-2-macroglobulin (α2M) in the presence of light and determined the functional alteration and conformational modifications induced in α2M structure. α2M is a highly abundant homotetrameric antiproteinase glycoprotein having diverse functions. Our result suggests α2M loses almost 54% of its proteinase inhibitory activity after 2 h incubation with gallic acid in presence of light. The inactivation of α2M was due to photodynamic generation of superoxide radical and hydrogen peroxide by gallic acid. The UV/visible absorption spectra of α2M showed increase in absorbance due to complex formation with gallic acid. Intrinsic fluorescence study shows that α2M-gallic acid interaction leads to quenching of fluorescence intensity of α2M and the mechanism of quenching is found to be static in nature. Synchronous fluorescence measurements reveal that gallic acid interaction leads to change in the microenvironment around tryptophan residues of α2M. Moreover, Fourier transform infrared spectroscopy and circular dichroism spectra suggests perturbation in secondary structure of α2M. Binding parameters were investigated by spectroscopic as well as calorimetric measurements. Negative value of enthalpy change and Gibbs free energy confirms the binding process to be exothermic and spontaneous.

Deciphering the binding of dutasteride with human alpha-2-macroglobulin: Molecular docking and calorimetric approach.

Dutasteride is a pharmacologically important drug employed to treat prostate cancer. Alpha-2-macroglobulin (α2M) is the primary proteinase inhibitor and is abundant in vertebrate plasma. Previous studies have shown that α2M levels were down regulated in prostate cancer. Our results of functional assay shows 50% decrease in the antiproteolytic potential ofα2Mupon its interaction with dutasteride. Fluorescence quenching revealed that dutasteride binds with α2M via static mechanism, resulting in the formation of dutasteride-α2M complex. Synchronous fluorescence studies suggest alteration in the microenvironment around tryptophan residues. Changes in the UV-visible spectra hints at formation of complex between the drug and protein. Secondary structural perturbations in α2M are confirmed by circular dichroism studies. Molecular docking discloses the involvement of hydrogen bonding during the interaction process and suggests the site of interaction of dutasteride on α2M monomer as Asn173, Lys171, Asp1178, Lys1236, His1182, Lys1177, Ser1180 and Lys1240.Isothermal titration calorimetry affirms the binding process to be spontaneous and exothermic. The results of this study may potentially be important should it be shown that dutasteride interacts with α2M under physiological conditions.

GenESysV: a fast, intuitive and scalable genome exploration open source tool for variants generated from high-throughput sequencing projects.

BACKGROUND: High throughput sequencing technologies have been increasingly used in basic genetic research as well as in clinical applications. More and more variants underlying Mendelian and complex diseases are being discovered and documented using these technologies. However, identifying and obtaining a short list of candidate disease-causing variants remains challenging for most of the users after variant calling, especially for people without computational skills. RESULTS: We developed GenESysV (Genome Exploration System for Variants) as a scalable, intuitive and user-friendly open source tool. It can be used in any high throughput sequencing or genotyping project for storing, managing, prioritizing and efficient retrieval of variants of interest. GenESysV is designed for use by researchers from a wide range of disciplines and computational skills, including wet-lab scientists, clinicians, and bioinformaticians. CONCLUSIONS: GenESysV is the first tool to be able to handle genomic variant dataset ranging in size from a few to thousands of samples and still maintain fast data importation and good query performance. It has a very intuitive graphical user interface and can also be used in studies where secured data access is an important concern. We believe this tool will benefit the human disease research community to speed up discoveries for genetic variants underlying human genetic disorders.