scholarly journals Natural compounds as potential PI3K-AKT1 signaling pathway inhibitors by means of pharmacophore modeling

2016 ◽  
Author(s):  
Serena Dotolo ◽  
Angelo Gaeta ◽  
Angelo Facchiano
Keyword(s):  
Protein Interactions ◽  
Chemical Properties ◽  
Natural Compounds ◽  
Pharmacophore Modeling ◽  
Bioactive Molecules ◽  
Allosteric Inhibitors ◽  
Protein Ligand Interactions ◽  
Zinc Database ◽  
Complex Protein ◽  
Ligand Interactions

AKT1, a modulator of PI3K-AKT1 pathway, is dysregulated in several human diseases, and understanding deeper its role in the complexity of biological systems remains an important goal. The research has been focused on development and study of potential synthetic-natural allosteric inhibitors for AKT1, and recent studies have shown how some natural compounds may play this role (1). We are interested in a screening of small bioactive molecules, in order to identify the potential “lead compounds”, for next experimental assays, searching those potentially able to inhibit AKT1 and its signaling mechanisms, trying to re-establish the normal balance and safeguarding of human health. The workflow executed is the following: 1) search in PDB database of a model structure for AKT1 (comparing different structures and choosing the most suitable for our purposes), through algorithm BLAST. 2) pharmacophore modeling by means of ZINCpharmer web-server, to investigate all purchasable compounds of the ZINC database, using the Pharmer as efficient and exact pharmacophore search technology (2). 3) screening of possible natural AKT1 inhibitors, using the pharmacophore generated by ZINCpharmer, choosing only the best candidates for next steps. 4) molecular validation of selected compounds, to analyze the ligand-protein interactions. 5) study of physical-chemical properties of selected compounds to trace their origin. 6)prediction of their biosynthetic pathways and Pharmacokinetics/Pharmacodynamics models, by means of ADMET/toxicity predictor server in order to direct the design of next experimental assays. Our attention is focused on the study of natural compounds that can show many health benefits, through the realization and analysis of “pharmacophore modeling”, essential step in drug discovery (3). We selected the PDB structure 3O96 as the reference complex (protein-ligand), and we analyzed it by means of ZINCpharmer, to generate three different “pharmacophore models” with three different list of natural compounds. It is performed a thorough screening of compounds applying other filters, to find some good candidates as possible natural AKT1 allosteric inhibitors. The compounds that match a well-defined pharmacophore have been analyzed through direct molecular docking, for selecting only the best candidates and studying the protein-ligand interactions. Selected compounds have been investigated in more details, to trace their origin, by their chemical-physical properties. This information can help us to predict some plausible enzyme-catalyzed reaction pathways, investigated with PathPred server and KEGG compound database, in order to highlight the most important reactions for biosynthesis of compounds and obtain PharmacoKinetics/PharmacoDynamics (PK/PD) models through ADME predictor server and to realize of next experimental assays. (Abstract truncated at 3,000 characters - the full version is available in the pdf file)

scholarly journals Natural compounds as potential PI3K-AKT1 signaling pathway inhibitors by means of pharmacophore modeling

2016 ◽  
Author(s):  
Serena Dotolo ◽  
Angelo Gaeta ◽  
Angelo Facchiano
Keyword(s):  
Protein Interactions ◽  
Chemical Properties ◽  
Natural Compounds ◽  
Pharmacophore Modeling ◽  
Bioactive Molecules ◽  
Allosteric Inhibitors ◽  
Protein Ligand Interactions ◽  
Zinc Database ◽  
Complex Protein ◽  
Ligand Interactions

AKT1, a modulator of PI3K-AKT1 pathway, is dysregulated in several human diseases, and understanding deeper its role in the complexity of biological systems remains an important goal. The research has been focused on development and study of potential synthetic-natural allosteric inhibitors for AKT1, and recent studies have shown how some natural compounds may play this role (1). We are interested in a screening of small bioactive molecules, in order to identify the potential “lead compounds”, for next experimental assays, searching those potentially able to inhibit AKT1 and its signaling mechanisms, trying to re-establish the normal balance and safeguarding of human health. The workflow executed is the following: 1) search in PDB database of a model structure for AKT1 (comparing different structures and choosing the most suitable for our purposes), through algorithm BLAST. 2) pharmacophore modeling by means of ZINCpharmer web-server, to investigate all purchasable compounds of the ZINC database, using the Pharmer as efficient and exact pharmacophore search technology (2). 3) screening of possible natural AKT1 inhibitors, using the pharmacophore generated by ZINCpharmer, choosing only the best candidates for next steps. 4) molecular validation of selected compounds, to analyze the ligand-protein interactions. 5) study of physical-chemical properties of selected compounds to trace their origin. 6)prediction of their biosynthetic pathways and Pharmacokinetics/Pharmacodynamics models, by means of ADMET/toxicity predictor server in order to direct the design of next experimental assays. Our attention is focused on the study of natural compounds that can show many health benefits, through the realization and analysis of “pharmacophore modeling”, essential step in drug discovery (3). We selected the PDB structure 3O96 as the reference complex (protein-ligand), and we analyzed it by means of ZINCpharmer, to generate three different “pharmacophore models” with three different list of natural compounds. It is performed a thorough screening of compounds applying other filters, to find some good candidates as possible natural AKT1 allosteric inhibitors. The compounds that match a well-defined pharmacophore have been analyzed through direct molecular docking, for selecting only the best candidates and studying the protein-ligand interactions. Selected compounds have been investigated in more details, to trace their origin, by their chemical-physical properties. This information can help us to predict some plausible enzyme-catalyzed reaction pathways, investigated with PathPred server and KEGG compound database, in order to highlight the most important reactions for biosynthesis of compounds and obtain PharmacoKinetics/PharmacoDynamics (PK/PD) models through ADME predictor server and to realize of next experimental assays. (Abstract truncated at 3,000 characters - the full version is available in the pdf file)

IN SILICO PREDICTION OF PROTEIN-LIGAND INTERACTIONS

2020 ◽  
pp. 254-256
Author(s):  
D. Filimonov ◽  
B. Sobolev ◽  
A. Lagunin
Keyword(s):  
Protein Interactions ◽  
Drug Targets ◽  
High Efficiency ◽  
Amino Acid Sequences ◽  
In Silico Prediction ◽  
Computer Prediction ◽  
Protein Ligand Interactions ◽  
Small Molecule Ligands ◽  
Ligand Interactions ◽  
Structural Descriptions

The method for computer prediction of protein-ligand interactions was developed. The amino acid sequences of target proteins and structural descriptions of small molecule ligands are used as the input data. The method was tested on protein families representing perspective drug targets. The developed approach allows one to predict ligand-protein interactions with high efficiency.

scholarly journals Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction

2019 ◽  
Author(s):  
Brent W. Anderson ◽  
Kuanqing Liu ◽  
Christine Wolak ◽  
Katarzyna Dubiel ◽  
Kenneth A. Satyshur ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Protein Interactions ◽  
Binding Motif ◽  
Protein Ligand Interactions ◽  
Protein Interfaces ◽  
Ligand Interactions ◽  
Binding Residues ◽  
The Common ◽  
Ligand Regulation

ABSTRACTThe signaling ligand (p)ppGpp binds diverse targets across bacteria, yet the mechanistic and evolutionary basis underlying these ligand-protein interactions remains poorly understood. Here we identify a novel (p)ppGpp binding motif in the enzyme HPRT, where (p)ppGpp shares identical binding residues for PRPP and nucleobase substrates to regulate purine homeostasis. Intriguingly, HPRTs across species share the conserved binding site yet strongly differ in ligand binding, from strong inhibition by basal (p)ppGpp levels to weak regulation at induced concentrations. Surprisingly, strong ligand binding requires an HPRT dimer-dimer interaction that allosterically opens the (p)ppGpp pocket. This dimer-dimer interaction is absent in the common ancestor but evolved to favor (p)ppGpp binding in the vast majority of bacteria. We propose that the evolutionary plasticity of oligomeric interfaces enables allosteric adjustment of ligand regulation, bypassing constraints of the ligand binding site. Since most ligands bind near protein-protein interfaces, this principle likely extends to other protein-ligand interactions.

scholarly journals Uses of Phage Display in Agriculture: A Review of Food-Related Protein-Protein Interactions Discovered by Biopanning over Diverse Baits

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Rekha Kushwaha ◽  
Christina M. Payne ◽  
A. Bruce Downie
Keyword(s):  
Phage Display ◽  
Protein Interactions ◽  
Biofuel Production ◽  
Food Allergies ◽  
Protein Protein Interactions ◽  
Patient Response ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Repair Mechanisms ◽  
Complex Polymers

This review highlights discoveries made using phage display that impact the use of agricultural products. The contribution phage display made to our fundamental understanding of how various protective molecules serve to safeguard plants and seeds from herbivores and microbes is discussed. The utility of phage display for directed evolution of enzymes with enhanced capacities to degrade the complex polymers of the cell wall into molecules useful for biofuel production is surveyed. Food allergies are often directed against components of seeds; this review emphasizes how phage display has been employed to determine the seed component(s) contributing most to the allergenic reaction and how it has played a central role in novel approaches to mitigate patient response. Finally, an overview of the use of phage display in identifying the mature seed proteome protection and repair mechanisms is provided. The identification of specific classes of proteins preferentially bound by such protection and repair proteins leads to hypotheses concerning the importance of safeguarding the translational apparatus from damage during seed quiescence and environmental perturbations during germination. These examples, it is hoped, will spur the use of phage display in future plant science examining protein-ligand interactions.

scholarly journals Entropy in molecular recognition by proteins

2017 ◽  
Vol 114 (25) ◽  
pp. 6563-6568 ◽  
Author(s):  
José A. Caro ◽  
Kyle W. Harpole ◽  
Vignesh Kasinath ◽  
Jackwee Lim ◽  
Jeffrey Granja ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Protein Interactions ◽  
Nmr Relaxation ◽  
Quantitative Relationship ◽  
Accessible Surface Area ◽  
Conformational Entropy ◽  
General Role ◽  
High Affinity ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein–ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein–ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein–ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for conformational entropy or “entropy meter” also allows for refinement of the contributions of solvent entropy and the loss in rotational-translational entropy accompanying formation of high-affinity complexes. Furthermore, structure-based application of the approach can also provide insight into long-lived specific water–protein interactions that escape the generic treatments of solvent entropy based simply on changes in accessible surface area. These results provide a comprehensive and unified view of the general role of entropy in high-affinity molecular recognition by proteins.

scholarly journals Virtual Docking of VBP1 with HBX and NFκB Protein to Study the Activation of NFκB in the Regulatory Mechanism of Liver Cancer

2021 ◽  
pp. 21-28
Author(s):  
Mamta Sagar ◽  
Padma Saxena ◽  
Suruchi Singh ◽  
Ravindra Nath ◽  
Pramod W. Ramteke
Keyword(s):  
Amino Acids ◽  
Liver Cancer ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Von Hippel Lindau ◽  
Hbv Replication ◽  
Protein Ligand Interactions ◽  
B Virus ◽  
Ligand Interactions ◽  
The Common

Molecular docking is an efficient way to study protein-protein and protein-ligand interactions in virtual mode, this provides structural annotations of molecular interactions, required in the drug discovery process. The Cartesian FFT approach in ‘Hex’ spherical polar Fourier (SPF) uses rotational correlations, this method is used here to study protein-protein interactions. Hepatitis B virus (HBV) X protein (HBx) is essential for virus infection and has been used in the development of therapeutics for liver cancer. It can interact with many cellular proteins. It interferes with cell viability and stimulates HBV replication. The von Hippel-Lindau binding protein 1(VBP1) has an important role in HBx-mediated nuclear factor kappa B (NFkB) stimulation. VBP1 and HBx function as coactivators in the activation of NFκB binding. Docking results revealed that HBx and NFkB bind with VBP1 at the common site on amino acids positions Arg 161, Glu 92, and Arg 82, which may have a role in HBx-mediated NFκB activation. Lowest energy complex VBP1- NFkB1 was obtained at -883.70 Kcal/mol. The amino acids involved in interaction among HBx, VBP1, and NFκB proteins, may be involved in transcriptional regulation and has significance in normal and abnormal regulation. These amino acid interactions may be associated with the manifestation of Liver cancer.

scholarly journals Identification of Novel Inhibitors for TG2 (Tissue Transglutaminase) and DJ-1 (Protein Deglycase) against Parkinson's Diseases by Pharmacophore-based Approaches

2020 ◽  
pp. 509-516
Author(s):  
GAYATRI S. VAIDYA ◽  
V. UMAKANTH NAIK ◽  
Prachi Parvatikar
Keyword(s):  
Molecular Docking ◽  
Clinical Symptoms ◽  
Tissue Transglutaminase ◽  
Pharmacophore Modeling ◽  
Protein Ligand Interactions ◽  
Parkinson’S Diseases ◽  
In Silico Admet ◽  
Ligand Interactions ◽  
The Central Nervous System ◽  
Docking Protein

Parkinson’s disease (PD) is a one of the most common neurodegenerative disease affecting the central nervous system (CNS) characterized by the multitude of motor and non-motor clinical symptoms. The hallmark of PD motor manifestation include progressive tremor, rigidity, brady kinesia and postural instability. There are many protein involved in the progression of this dieses including TG2 and DJ-1 protein. The present is focused on finding the novel inhibitor based from phytochemicals catagory to inhibit activity of TG2 and DJ-1 protein. The Cheminformatics pipeline used which include ADMET analysis,pharmacophore modeling and molecular docking. Six best hit molecules were mapped with the E-pharmacophore features of TG2 and DJ-1 protein. These pharmacophore were further analysed by molecular docking, protein–ligand interactions and in silico ADMET studies. The molecular docking analysis revealed that hydroxywogonin and 2',3',5,7-Tetrahydroxy flavones had good binding energy and satisfied the Lipinski rule of five and had no toxicity.

Imaginative Order from Reasonable Chaos: Conformation-Driven Activity and Reactivity in Exploring Protein–Ligand Interactions

2018 ◽  
Vol 71 (12) ◽  
pp. 917
Author(s):  
Alexander F. Moore ◽  
David J. Newman ◽  
Shoba Ranganathan ◽  
Fei Liu
Keyword(s):  
Natural Product ◽  
Conformational Dynamics ◽  
Chemical Properties ◽  
Protein Domains ◽  
Lead Discovery ◽  
Protein Ligand Interactions ◽  
Structural Framework ◽  
Drug Lead ◽  
Conformational Diversity ◽  
Ligand Interactions

Sir Derek Barton’s seminal work on steroid conformational analysis opened up a new era of enquiry into how the preferred conformation of any molecule could have profound effects on its physical–chemical properties and activities. Conformation-based effects on molecular activity and reactivity continue to manifest, with one key area of investigation currently focussed on conformational entropy in driving protein–ligand interactions. Carrying on from Barton’s initial insight on natural product conformational properties, new questions now address how conformational flexibility within a bioactive natural product structural framework (reasonable chaos), can be directed to confer dynamically new protein–ligand interactions beyond the basic lock–key model (imaginative order). Here we summarise our work on exploring conformational diversity from fluorinated natural product fragments, and how this approach of conformation-coupled diversity-oriented synthesis can be used to iteratively derive ligands with enhanced specificity against highly homologous protein domains. Our results demonstrate that the conformation entropic states of highly conserved protein domains differ significantly, and this conformational diversity, beyond primary sequence analysis, can be duly captured and exploited by natural-product derived ligands with complementary conformational dynamics for enhancing recognition specificity in drug lead discovery.

Measures of cooperativity in the binding of ligands to proteins and their relation to non-additivity in protein-protein interactions

1986 ◽  
Vol 229 (1256) ◽  
pp. 315-329 ◽  
Keyword(s):  
Protein Interactions ◽  
Proteinase Inhibitors ◽  
Interaction Constant ◽  
Hill Coefficient ◽  
Protein Protein Interactions ◽  
Thermodynamic Cycles ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Hill Coefficients ◽  
The Hill

The analogy between cooperativity in the binding of ligands to proteins and non-additivity in protein-protein interactions is demonstrated and discussed in terms of the Wong and the Hill coefficients. A measure of non-additivity, the interaction constant , is rigorously derived for four thermodynamic cycles, involving the binding of small molecules to proteins and protein association. It is the reciprocal of the 1 defect factor of Laskowski et al. in Proteinase inhibitors: medical and biological aspects (ed. N. Katunuma et al.), pp. 55-68 (1983), andits logarithm is the Wong measure of cooperativity. These three measures are thus here given a common theoretical basis. The Hill coefficient for an asymmetric dimer that binds two different ligands which do not compete for the same site, at 50% saturation of each site, is derived. It is shown to be a function of the interaction constant and of the fraction of protein to which ligand is bound at both sites. These relations for protein-ligand interactions are then discussed in the context of non-additivity in protein-protein interactions.

Sign in / Sign up

Export Citation Format

Share Document