Molecular Modeling and Active Site Binding Mode Characterization of Aspartate β-Semialdehyde Dehydrogenase Family

2013 ◽  
Vol 32 (4) ◽  
pp. 377-383 ◽  
Author(s):  
Rajender Kumar ◽  
Prabha Garg
Keyword(s):  
Molecular Modeling ◽  
Active Site ◽  
Binding Mode ◽  
Semialdehyde Dehydrogenase ◽  
Site Binding

scholarly journals Structural and Functional Characterization of the Human Thymidylate Synthase (hTS) Interface Variant R175C, New Perspectives for the Development of hTS Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1362
Author(s):  
Cecilia Pozzi ◽  
Stefania Ferrari ◽  
Rosaria Luciani ◽  
Maria Costi ◽  
Stefano Mangani
Keyword(s):  
Thymidylate Synthase ◽  
Active Site ◽  
Functional Characterization ◽  
Binding Mode ◽  
Anticancer Chemotherapy ◽  
Innovative Strategies ◽  
X Ray Crystallography ◽  
Site Targeting ◽  
New Strategies

Human thymidylate synthase (hTS) is pivotal for cell survival and proliferation, indeed it provides the only synthetic source of dTMP, required for DNA biosynthesis. hTS represents a validated target for anticancer chemotherapy. However, active site-targeting drugs towards hTS have limitations connected to the onset of resistance. Thus, new strategies have to be applied to effectively target hTS without inducing resistance in cancer cells. Here, we report the generation and the functional and structural characterization of a new hTS interface variant in which Arg175 is replaced by a cysteine. Arg175 is located at the interface of the hTS obligate homodimer and protrudes inside the active site of the partner subunit, in which it provides a fundamental contribution for substrate binding. Indeed, the R175C variant results catalytically inactive. The introduction of a cysteine at the dimer interface is functional for development of new hTS inhibitors through innovative strategies, such as the tethering approach. Structural analysis, performed through X-ray crystallography, has revealed that a cofactor derivative is entrapped inside the catalytic cavity of the hTS R175C variant. The peculiar binding mode of the cofactor analogue suggests new clues exploitable for the design of new hTS inhibitors.

scholarly journals Sequence characterization and molecular modeling of clinically relevant variants of the SARS-CoV-2 main protease

2020 ◽  
Author(s):  
Thomas J. Cross ◽  
Gemma R. Takahashi ◽  
Elizabeth M. Diessner ◽  
Marquise G. Crosby ◽  
Vesta Farahmand ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Active Site ◽  
Viral Evolution ◽  
Specific Substrate ◽  
Inhibitor Design ◽  
Hydrophobic Residues ◽  
Sequence Characterization ◽  
Main Protease ◽  
Residue Substitution

The SARS-CoV-2 main protease (Mpro) is essential to viral replication and cleaves highly specific substrate sequences, making it an obvious target for inhibitor design. However, as for any virus, SARS-CoV-2 is subject to constant selection pressure, with new Mpro mutations arising over time. Identification and structural characterization of Mpro variants is thus critical for robust inhibitor design. Here we report sequence analysis, structure predictions, and molecular modeling for seventy-nine Mpro variants, constituting all clinically observed mutations in this protein as of April 29, 2020. Residue substitution is widely distributed, with some tendency toward larger and more hydrophobic residues. Modeling and protein structure network analysis suggest differences in cohesion and active site flexibility, revealing patterns in viral evolution that have relevance for drug discovery.

A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway

2014 ◽  
Vol 70 (12) ◽  
pp. 3244-3252 ◽  
Author(s):  
Alexander G. Pavlovsky ◽  
Bharani Thangavelu ◽  
Pravin Bhansali ◽  
Ronald E. Viola
Keyword(s):  
Active Site ◽  
Enzyme Inhibitor ◽  
Bacterial Survival ◽  
Cautionary Tale ◽  
Lead Compounds ◽  
Semialdehyde Dehydrogenase ◽  
Fragment Library ◽  
Aspartate Pathway ◽  
Essential Enzyme

The aspartate pathway is essential for the production of the amino acids required for protein synthesis and of the metabolites needed in bacterial development. This pathway also leads to the production of several classes of quorum-sensing molecules that can trigger virulence in certain microorganisms. The second enzyme in this pathway, aspartate β-semialdehyde dehydrogenase (ASADH), is absolutely required for bacterial survival and has been targeted for the design of selective inhibitors. Fragment-library screening has identified a new set of inhibitors that, while they do not resemble the substrates for this reaction, have been shown to bind at the active site of ASADH. Structure-guided development of these lead compounds has produced moderate inhibitors of the target enzyme, with some selectivity observed between the Gram-negative and Gram-positive orthologs of ASADH. However, many of these inhibitor analogs and derivatives have not yet achieved the expected enhanced affinity. Structural characterization of these enzyme–inhibitor complexes has provided detailed explanations for the barriers that interfere with optimal binding. Despite binding in the same active-site region, significant changes are observed in the orientation of these bound inhibitors that are caused by relatively modest structural alterations. Taken together, these studies present a cautionary tale for issues that can arise in the systematic approach to the modification of lead compounds that are being used to develop potent inhibitors.

Complexed and ligand-free high-resolution structures of urate oxidase (Uox) fromAspergillus flavus: a reassignment of the active-site binding mode

2004 ◽  
Vol 60 (3) ◽  
pp. 453-462 ◽  
Author(s):  
Pascal Retailleau ◽  
Nathalie Colloc'h ◽  
Denis Vivarès ◽  
Françoise Bonneté ◽  
Bertrand Castro ◽  
...  
Keyword(s):  
High Resolution ◽  
Active Site ◽  
Binding Mode ◽  
Urate Oxidase ◽  
Ligand Free ◽  
Site Binding

Protein modeling and active site binding mode interactions of myrosinase–sinigrin in Brassica juncea—An in silico approach

2011 ◽  
Vol 29 (5) ◽  
pp. 740-746 ◽  
Author(s):  
Rajender Kumar ◽  
Sandeep Kumar ◽  
Seema Sangwan ◽  
Inderjit Singh Yadav ◽  
Rakesh Yadav
Keyword(s):  
Brassica Juncea ◽  
Active Site ◽  
In Silico ◽  
Binding Mode ◽  
Protein Modeling ◽  
Mode Interactions ◽  
Site Binding

(R)-3-Amidinophenylalanine-Derived Inhibitors of Factor Xa with a Novel Active-Site Binding Mode

2002 ◽  
Vol 383 (7-8) ◽  
Author(s):  
M. M. Mueller ◽  
S. Sperl ◽  
J. Stürzebecher ◽  
W. Bode ◽  
L. Moroder
Keyword(s):  
Active Site ◽  
Factor Xa ◽  
Binding Mode ◽  
Site Binding

Characterization of an Abnormal Antithrombin (Milano 2) with Defective Thrombin Binding

1986 ◽  
Vol 56 (03) ◽  
pp. 349-352 ◽  
Author(s):  
A Tripodi ◽  
A Krachmalnicoff ◽  
P M Mannucci
Keyword(s):  
Venous Thromboembolism ◽  
Active Site ◽  
Inhibitory Activity ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Molecular Defect ◽  
Affinity Adsorption ◽  
Italian Family ◽  
Crossed Immunoelectrophoresis

SummaryFour members of an Italian family (two with histories of venous thromboembolism) had a qualitative defect of antithrombin III reflected by normal antigen concentrations and halfnormal antithrombin activity with or without heparin. Anti-factor Xa activities were consistently borderline low (about 70% of normal). For the propositus’ plasma and serum the patterns of antithrombin III in crossed-immunoelectrophoresis with or without heparin were indistinguishable from those of normal plasma or serum. A normal affinity of antithrombin III for heparin was documented by heparin-sepharose chromatography. Affinity adsorption of the propositus’ plasma to human α-thrombin immobilized on sepharose beads revealed defective binding of the anti thrombin III to thrombin-sepharose. Hence the molecular defect of this variant appears to be at the active site responsible for binding and neutralizing thrombin, thus accounting for the low thrombin inhibitory activity.

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