scholarly journals PvP01-DB: computational structural and functional characterization of soluble proteome of PvP01 strain of Plasmodium vivax

Database ◽  
2020 ◽  
Vol 2020 ◽  
Author(s):  
Ankita Singh ◽  
Rahul Kaushik ◽  
Dheeraj Kumar Chaurasia ◽  
Manpreet Singh ◽  
B Jayaram
Keyword(s):  
Plasmodium Vivax ◽  
Drug Targets ◽  
Active Sites ◽  
Functional Characterization ◽  
Complete Information ◽  
Drug Candidates ◽  
Web Resource ◽  
Quantum Leap ◽  
Public Resources ◽  
Cellular Components

Abstract Despite Plasmodium vivax being the main offender in the majority of malarial infections, very little information is available about its adaptation and development in humans. Its capability for activating relapsing infections through its dormant liver stage and resistance to antimalarial drugs makes it as one of the major challenges in eradicating malaria. Noting the immediate necessity for the availability of a comprehensive and reliable structural and functional repository for P. vivax proteome, here we developed a web resource for the new reference genome, PvP01, furnishing information on sequence, structure, functions, active sites and metabolic pathways compiled and predicted using some of the state-of-the-art methods in respective fields. The PvP01 web resource comprises organized data on the soluble proteome consisting of 3664 proteins in blood and liver stages of malarial cycle. The current public resources represent only 163 proteins of soluble proteome of PvP01, with complete information about their molecular function, biological process and cellular components. Also, only 46 proteins of P. vivax have experimentally determined structures. In this milieu of extreme scarcity of structural and functional information, PvP01 web resource offers meticulously validated structures of 3664 soluble proteins. The sequence and structure-based functional characterization led to a quantum leap from 163 proteins available presently to whole soluble proteome offered through PvP01 web resource. We believe PvP01 web resource will serve the researchers in identifying novel protein drug targets and in accelerating the development of structure-based new drug candidates to combat malaria. Database Availability: http://www.scfbio-iitd.res.in/PvP01

In Silico Prediction and Validation of Oxygen-Regulated Protein N-myc Downstream Regulated Gene 3 and Virtual Screening of Competitive Inhibitors of L-Lactate as Therapeutics

2019 ◽  
Vol 16 (6) ◽  
pp. 637-644
Author(s):  
Hongyu Cao ◽  
Yanhua Wu ◽  
Xingzhi Zhou ◽  
Xuefang Zheng ◽  
Ge Jiang
Keyword(s):  
Active Sites ◽  
Competitive Inhibition ◽  
Hydrophobic Effect ◽  
3D Structure ◽  
Amino Acid Residues ◽  
In Silico Prediction ◽  
Hypoxic Response ◽  
Drug Candidates ◽  
Competitive Inhibitors ◽  
Extracellular Regulated Protein Kinases

Background: N-myc downstream regulated gene 3 (NDRG3) is a newly discovered oxygen-regulated protein which will bind with L-Lactate in hypoxia and further activate Raf (rapidly accelerated fibrosarcoma)-ERK (extracellular regulated protein kinases) pathway, promoting cell growth and angiogenesis. Methods: Competitive inhibition on the binding of NDRG3 and L-Lactate may be potentially a useful strategy for the repression of hypoxic response mediated by NDRG3. The threedimensional (3D) structure of NDRG3 was built by using homology modeling for its crystal structure was not available. Then, L-Lactate was docked into NDRG3, from which we knew it bound with amino acid residues Gln69, His183, Asn189, Ala72 and Pro66 of NDRG3 in the most possible active sites. Approximately 3000 compounds have been virtually screened and the 6 topranked compounds were selected as reference molecules to analyze their interaction relationships, which illustrated that some of them might form electrostatic interaction with Glu70 and Asp187, π-&π stack with Phe75 and Tyr180, hydrogen bonds with Gly71 and Asn189, hydrophobic effect with Ala72 and Ile184. Results: Novel molecules were designed through structural optimization of the 6 top-ranked compounds and subsequently their ADMET properties were predicted. Conclusion: These molecules may be potential drug candidates for the suppression of hypoxic response mediated by NDRG3 and targeted therapy for hypoxia-induced diseases.

Covid 19 – Structural proteins and prospective drug candidates (Preprint)

2020 ◽  
Author(s):  
A.N Anoopkumar ◽  
Sharrel Rebello ◽  
Embalil Mathachan Aneesh
Keyword(s):  
Causative Agent ◽  
Protein Level ◽  
Drug Targets ◽  
Current Paper ◽  
Structural Proteins ◽  
Drug Candidates ◽  
Propagation Properties

UNSTRUCTURED Covid 19 the causative agent of the current devastating pandemic has turned out to be a notorious virus to all men-irrespective of either common to scientific calibre. Attempts to combat this deadly virus are the need of the hour and quite often the best way to defeat an opponent is to keenly study about its structural and propagation properties. The current paper describes briefly Covid 19 at the genomic, structural and protein level to the best of our knowledge. Furthermore, the prospects of possible drug targets that could aid in the control of this virus are also discussed.

scholarly journals In silico characterization and structural modeling of bacterial metalloprotease of family M4

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rajnee Hasan ◽  
Md. Nazmul Haq Rony ◽  
Rasel Ahmed
Keyword(s):  
Drug Targets ◽  
Active Sites ◽  
Pathogenic Bacteria ◽  
Tertiary Structure ◽  
Transmembrane Helix ◽  
Confidence Score ◽  
Potential Drug ◽  
Protein Protein Interaction ◽  
Industrial Level ◽  
Potential Drug Targets

Abstract Background The M4 family of metalloproteases is comprised of a large number of zinc-containing metalloproteases. A large number of these enzymes are important virulence factors of pathogenic bacteria and therefore potential drug targets. Whereas some enzymes have potential for biotechnological applications, the M4 family of metalloproteases is known almost exclusively from bacteria. The aim of the study was to identify the structure and properties of M4 metalloprotease proteins. Results A total of 31 protein sequences of M4 metalloprotease retrieved from UniProt representing different species of bacteria have been characterized for various physiochemical properties. They were thermostable, hydrophillic protein of a molecular mass ranging from 38 to 66 KDa. Correlation on the basis of both enzymes and respective genes has also been studied by phylogenetic tree. B. cereus M4 metalloprotease (PDB ID: 1NPC) was selected as a representative species for secondary and tertiary structures among the M4 metalloprotease proteins. The secondary structure displaying 11 helices (H1-H11) is involved in 15 helix-helix interactions, while 4 β-sheet motifs composed of 15 β-strands in PDBsum. Possible disulfide bridges were absent in most of the cases. The tertiary structure of B. cereus M4 metalloprotease was validated by QMEAN4 and SAVES server (Ramachandran plot, verify 3D, and ERRAT) which proved the stability, reliability, and consistency of the tertiary structure of the protein. Functional analysis was done in terms of membrane protein topology, disease-causing region prediction, proteolytic cleavage sites prediction, and network generation. Transmembrane helix prediction showed absence of transmembrane helix in protein. Protein-protein interaction networks demonstrated that bacillolysin of B. cereus interacted with ten other proteins in a high confidence score. Five disorder regions were identified. Active sites analysis showed the zinc-binding residues—His-143, His-147, and Glu-167, with Glu-144 acting as the catalytic residues. Conclusion Moreover, this theoretical overview will help researchers to get a details idea about the protein structure and it may also help to design enzymes with desirable characteristics for exploiting them at industrial level or potential drug targets.

scholarly journals Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

2021 ◽  
pp. 1-10
Author(s):  
Vera Kovaleva ◽  
Mart Saarma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Dopamine Neurons ◽  
Drug Candidates ◽  
The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

Developing novel chemical entities for the treatment of lysosomal storage disorders: an academic perspective

2015 ◽  
Vol 309 (12) ◽  
pp. F996-F999 ◽  
Author(s):  
James A. Shayman
Keyword(s):  
Drug Targets ◽  
Lysosomal Storage ◽  
Federal Drug Administration ◽  
Drug Candidates ◽  
Gaucher Disease Type 1 ◽  
Biotechnology Companies ◽  
Approved Drugs ◽  
Novel Drug ◽  
Early Drug

Historically, most Federal Drug Administration-approved drugs were the result of “in-house” efforts within large pharmaceutical companies. Over the last two decades, this paradigm has steadily shifted as the drug industry turned to startups, small biotechnology companies, and academia for the identification of novel drug targets and early drug candidates. This strategic pivot has created new opportunities for groups less traditionally associated with the creation of novel therapeutics, including small academic laboratories, for engagement in the drug discovery process. A recent example of the successful development of a drug that had its origins in academia is eliglustat tartrate, an oral agent for Gaucher disease type 1.

scholarly journals SELDI ProteinChip®Array Technology: Protein-Based Predictive Medicine and Drug Discovery Applications

2003 ◽  
Vol 2003 (4) ◽  
pp. 237-241 ◽  
Author(s):  
Guru Reddy ◽  
Enrique A. Dalmasso
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Treatment Options ◽  
Drug Effects ◽  
Proteome Analysis ◽  
Predictive Medicine ◽  
Protein Drug ◽  
Proteinchip Array ◽  
Drug Candidates ◽  
Array Technology

Predictive medicine, utilizing the ProteinChip®Array technology, will develop through the implementation of novel biomarkers and multimarker patterns for detecting disease, determining patient prognosis, monitoring drug effects such as efficacy or toxicity, and for defining treatment options. These biomarkers may also serve as novel protein drug candidates or protein drug targets. In addition, the technology can be used for discovering small molecule drugs or for defining their mode of action utilizing protein-based assays. In this review, we describe the following applications of the ProteinChip Array technology: (1) discovery and identification of novel inhibitors of HIV-1 replication, (2) serum and tissue proteome analysis for the discovery and development of novel multimarker clinical assays for prostate, breast, ovarian, and other cancers, and (3) biomarker and drug discovery applications for neurological disorders.

scholarly journals Translational and Clinical Pharmacology Considerations in Drug Repurposing for X-linked Adrenoleukodystrophy-A Rare Peroxisomal Disorder

2021 ◽  
Author(s):  
Julianne Tieu ◽  
Siddhee Sahasrabudhe ◽  
Paul Orchard ◽  
James Cloyd ◽  
Reena Kartha
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Drug Repurposing ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Candidates ◽  
Target Patient Population ◽  
Site Of Action ◽  
Repurposed Drugs ◽  
Gait Disturbances ◽  
Spastic Quadriparesis

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

scholarly journals Membrane proteins: always an insoluble problem?

2016 ◽  
Vol 44 (3) ◽  
pp. 790-795 ◽  
Author(s):  
Andrea E. Rawlings
Keyword(s):  
Membrane Proteins ◽  
Lipid Membranes ◽  
Drug Targets ◽  
Functional Characterization ◽  
Water Soluble ◽  
High Yield ◽  
Cellular Processes ◽  
Native Sequence ◽  
Protein Research ◽  
New Methodologies

Membrane proteins play crucial roles in cellular processes and are often important pharmacological drug targets. The hydrophobic properties of these proteins make full structural and functional characterization challenging because of the need to use detergents or other solubilizing agents when extracting them from their native lipid membranes. To aid membrane protein research, new methodologies are required to allow these proteins to be expressed and purified cheaply, easily, in high yield and to provide water soluble proteins for subsequent study. This mini review focuses on the relatively new area of water soluble membrane proteins and in particular two innovative approaches: the redesign of membrane proteins to yield water soluble variants and how adding solubilizing fusion proteins can help to overcome these challenges. This review also looks at naturally occurring membrane proteins, which are able to exist as stable, functional, water soluble assemblies with no alteration to their native sequence.

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.

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