scholarly journals AutoGPA: An Automated 3D-QSAR Method Based on Pharmacophore Alignment and Grid Potential Analysis

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Naoyuki Asakawa ◽  
Seiichi Kobayashi ◽  
Junichi Goto ◽  
Noriaki Hirayama
Keyword(s):  
Prior Information ◽  
Three Dimensional ◽  
3D Qsar ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Active Molecule ◽  
Main Requirement ◽  
Qsar Models ◽  
Grid Potential ◽  
Real World Problems

3D-QSAR approach has been widely applied and proven to be useful in the case where no reliable crystal structure of the complex between a biologically active molecule and the receptor is available. At the same time, however, it also has highlighted the sensitivity of this approach. The main requirement of the traditional 3D-QSAR method is that molecules should be correctly overlaid in what is assumed to be the bioactive conformation. Identifying an active conformation of a flexible molecule is technically difficult. It has been a bottleneck in the application of the 3D-QSAR method. We have developed a 3D-QSAR software named AutoGPA especially based on an automatic pharmacophore alignment method in order to overcome this problem which has discouraged general medicinal chemists from applying the 3D-QSAR methods to their “real-world” problems. Applications of AutoGPA to three inhibitor-receptor systems have demonstrated that without any prior information about the three-dimensional structure of the bioactive conformations AutoGPA can automatically generate reliable 3D-QSAR models. In this paper, the concept of AutoGPA and the application results will be described.

scholarly journals A helminth chitinase structurally similar to mammalian chitinase displays immunomodulatory properties

2019 ◽  
Author(s):  
Friederike Ebner ◽  
Katja Balster ◽  
Katharina Janek ◽  
Agathe Niewienda ◽  
Piotr H. Malecki ◽  
...  
Keyword(s):  
Inflammatory Marker ◽  
Disease Model ◽  
Three Dimensional ◽  
Gastrointestinal Nematode ◽  
Airway Hyperreactivity ◽  
Allergic Airway Disease ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Trichuris Suis ◽  
Immunomodulatory Properties

AbstractPreviously, we reported significant immunomodulatory effects of the entire excretory-secretory (ES) proteins of the first larval stage (L1) of the gastrointestinal nematodeTrichuris suisin a rodent model of allergic hyperreactivity. In the present study, we aimed to identify the proteins accounting for the modulatory effects of theT. suisL1 ES proteins and thus studied selected components for their immunomodulatory efficacy in an OVA-induced allergic airway disease model. In particular, an enzymatically activeT. suischitinase mediated amelioration of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung. The three-dimensional structure of theT. suischitinase as determined by high-resolution X-ray crystallography revealed significant similarities to mouse acidic mammalian chitinase (AMCase). In addition, the unique ability ofT. suischitinase to form dimers, as well as acidic surface patches within the dimerization region may contribute to the formation of cross-reactive antibodies to the mouse homologs. This hypothesis is supported by the observation thatT. suischitinase treatment induced cross-reactive antibodies to mouse AMCase and chitinase-like protein BRP-39 in the AHR model. In conclusion, a biologically activeT. suischitinase exhibits immunomodulatory properties despite its structural similarity to the mammalian counterpart.Author summaryExperimental immunotherapy via reintroduction of intestinal worms to treat and prevent autoimmune, chronic inflammatory or allergic diseases is being discussed but the underlying mechanisms are still not fully understood. Here, we investigated the immunomodulatory potential of specific proteins of the whipwormTrichuris suisthat are secreted very early during larval development. Using a murine model of allergic lung disease, we show that in particular oneT. suisprotein, functionally characterized as an active chitinase, is reducing the lung inflammation. TheT. suischitinases three-dimensional protein structure revealed remarkable similarities to the hosts’ chitinase, an enzyme known to play a pivotal role in lung allergy. We also show that treatment with the helminth chitinase induced cross-reactive antibody responses against murine chitinase and chitinase-like proteins, both being inflammatory marker and regulators of type 2 immunity. Thus, our study provides a novel mechanism of immunomodulation by helminth components and may contribute to a better understanding of clinical responses of patients receiving helminthic therapy.

scholarly journals Dendrimers: A New Race of Pharmaceutical Nanocarriers

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Pooja Mittal ◽  
Anjali Saharan ◽  
Ravinder Verma ◽  
Farag M. A. Altalbawy ◽  
Mohammed A. Alfaidi ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Chemical Properties ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Synthesis Mechanism ◽  
Drug Conjugates ◽  
Wide Range ◽  
New Race ◽  
Physical And Chemical ◽  
And Chemical Properties

Dendrimers are nanosized, symmetrical molecules in which a small atom or group of atoms is surrounded by the symmetric branches known as dendrons. The structure of dendrimers possesses the greatest impact on their physical and chemical properties. They grow outwards from the core-shell which further reacts with monomers having one reactive or two dormant molecules. Dendrimers’ unique characteristics such as hyperbranching, well-defined spherical structure, and high compatibility with the biological systems are responsible for their wide range of applications including medical and biomedical areas. Particularly, the dendrimers’ three-dimensional structure can incorporate a wide variety of drugs to form biologically active drug conjugates. In this review, we focus on the synthesis, mechanism of drug encapsulations in dendrimers, and their wide applications in drug delivery.

scholarly journals Mutagenesis of Glu403 to Cys in rabbit neutral endopeptidase-24.11 (neprilysin) creates a disulphide-linked homodimer: analogy with endothelin-converting enzyme

1997 ◽  
Vol 327 (3) ◽  
pp. 925-929 ◽  
Author(s):  
V. Mien HOANG ◽  
E. Clare SANSOM ◽  
J. Anthony TURNER
Keyword(s):  
Three Dimensional ◽  
Neutral Endopeptidase ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Mutant Form ◽  
Converting Enzyme ◽  
Wild Type ◽  
Endopeptidase 24.11 ◽  
Reducing Conditions ◽  
Endothelin Converting Enzyme

Neutral endopeptidase-24.11 (NEP; neprilysin; EC 3.4.24.11) and endothelin-converting enzyme (ECE) are related zinc metallopeptidases involved in the processing of biologically active peptides. Only ECE, however, exists as a disulphide-linked homodimer. The covalent linkage in rat ECE is between Cys412 in each subunit, which is equivalent to Glu403 in rabbit NEP. Here we report that directed mutagenesis of Glu403 to cysteine in rabbit NEP creates a disulphide-linked homodimer, as revealed by transient transfection in COS-1 cells and SDS/PAGE of a membrane fraction. Under reducing conditions, both the mutant (E403C) and the wild-type NEP migrate as a polypeptide of 92 kDa. However, under non-reducing conditions, the Mr of the wild type remains unchanged, whereas that of the mutant is doubled. Co-transfection of wild-type ECE and E403C NEP cDNA did not result in the production of a NEP-ECE heterodimer. Comparison of the kinetic constants for wild-type and E403C mutant NEP with either [D-Ala2,Leu5]enkephalin or 3-carboxypropanoyl-alanyl-alanyl-leucine-4-nitroanilide (Suc-Ala-Ala-Leu-NH-Np) as substrate show a decrease of approx. 50% in Vmax/Km for the mutant form. The IC50 value for inhibition of the mutant by phosphoramidon or thiorphan is increased 3-fold and 5-fold respectively. Although NEP and ECE exhibit only about 40% identity and differ substantially in substrate specificity and some other characteristics, these data indicate that they have considerable similarity in three-dimensional structure, allowing dimer formation in the mutant NEP with the disulphide link probably occurring in a hydrophilic surface loop.

scholarly journals In Silicon Design of Antimicrobial Oligopeptides Based on 3D-QSAR Modelling and Bioassay Evaluation

2021 ◽  
Author(s):  
Guangping Li ◽  
Yuxuan Wang ◽  
Yan Shen ◽  
Haiqiong Guo ◽  
Qingxiu He ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Therapeutic Option ◽  
Three Dimensional ◽  
Similarity Index ◽  
3D Qsar ◽  
Field Analysis ◽  
Multi Drug Resistance ◽  
E Coli ◽  
Qsar Models ◽  
Lower Drug

Abstract The emergence of multi-drug resistance bacteria poses great health theat. Therefore, it is a crucial demand to obtain new antibacterial drugs. Antimicrobial peptides (AMPs) have the characteristics of wide antimicrobial spectrum and lower drug resistance, hence, it is hopeful to substitute for classical antibiotics. In this study, two classic methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), were used to analysis the structural feature of small AMPs against S. aureus or E. coli respectively. Subsequently, Three-Dimensional Quantitative Structure-Activity Relationships (3D-QSAR) models (for S. aureus, CoMFA: Q2 = 0.512, R2 = 0.943, F = 59.916; CoMSIA: Q2 = 0.645, R2 = 0.993, F = 339.242; for E. Coli, CoMFA: Q2 = 0.507, R2 = 0.913, F = 66.862; CoMSIA: Q2 = 0.573, R2 = 0.966, F = 96.84) with good predictability and stability were constructed. Seven novel small AMPs were designed and synthesized based on the theoretical model. The novel AMPs showed potent antibacterial activity against S. aureus and E. coli without causing host toxicity. Our findings provide a potential therapeutic option using 3D-QSAR models guiding the design and modification of novel AMPs, to address the prevalent infections caused by MDR bacterial.

scholarly journals Molecular modeling of acetylcholinesterase interaction with irreversible and reversible organophosphorous inhibitors

2011 ◽  
Vol 57 (1) ◽  
pp. 61-76 ◽  
Author(s):  
O.V. Tikhonova ◽  
V.S. Skvortsov ◽  
O.A. Raevsky
Keyword(s):  
Comparative Analysis ◽  
Molecular Modeling ◽  
Three Dimensional ◽  
Acetylcholinesterase Inhibitors ◽  
3D Qsar ◽  
Acetylcholinesterase Inhibition ◽  
Quality Model ◽  
Irreversible Inhibitors ◽  
Qsar Models ◽  
3D Fields

Three-dimensional Quantitative Structure-Аctivity Relationship models were designed for irreversible and reversible acetylcholinesterase inhibitors by molecular modeling methods. In case of irreversible inhibitors CoMFA (the comparative analysis of molecular fields) or CoMSIA (the comparative analysis of indexes of molecular similarity) descriptors together with HYBOT 3D fields provide more statistically valid 3D-QSAR models. This indicates importance of donor-acceptor interactions for irreversible acetylcholinesterase inhibition. In case of reversible organophosphorous inhibitors good quality model for structure-activity relationships was developed using CoMFA fields. The obtained models have good predictive power and can be used for estimation of new organophosphorous compounds inhibitor activity that in turn correlates with toxicity of these compounds.

scholarly journals Receptor Guided 3D-QSAR: A Useful Approach for Designing of IGF-1R Inhibitors

2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
M. Muddassar ◽  
F. A. Pasha ◽  
H. W. Chung ◽  
K. H. Yoo ◽  
C. H. Oh ◽  
...  
Keyword(s):  
Structural Information ◽  
Three Dimensional ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Field Analysis ◽  
Comparative Molecular Field Analysis ◽  
Qsar Studies ◽  
Similarity Indices ◽  
Qsar Models ◽  
Derivatives Of

Research by other investigators has established that insulin-like growth factor‐1 receptor (IGF-1R) is a key oncological target, and that derivatives of 1, 3-disubstituted-imidazo[1,5-] pyrazine are potent IGF-1R inhibitors. In this paper, we report on our three-dimensional quantitative structure activity relationship (3D-QSAR) studies for this series of compounds. We validated the 3D-QSAR models by the comparison of two major alignment schemes, namely, ligand-based (LB) and receptor-guided (RG) alignment schemes. The latter scheme yielded better 3D-QSAR models for both comparative molecular field analysis (CoMFA) (, ) and comparative molecular similarity indices analysis (CoMSIA) (, ). We submit that this might arise from the more accurate inhibitor alignment that results from using the structural information of the active site. We conclude that the receptor-guided 3D-QSAR may be helpful to design more potent IGF-1R inhibitors, as well as to understand their binding affinity with the receptor.

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