AutoPH4: An Automated Method for Generating Pharmacophore Models from Protein Binding Pockets

2020 ◽  
Vol 60 (9) ◽  
pp. 4326-4338 ◽  
Author(s):  
Siduo Jiang ◽  
Miklos Feher ◽  
Chris Williams ◽  
Brian Cole ◽  
David E. Shaw
Keyword(s):  
Protein Binding ◽  
Automated Method ◽  
Binding Pockets ◽  
Pharmacophore Models

scholarly journals Hybrid Dynamic Pharmacophore Models as Effective Tools to Identify Novel Chemotypes for Anti-TB Inhibitor Design: A Case Study With Mtb-DapB

2020 ◽  
Vol 8 ◽  
Author(s):  
Chinmayee Choudhury ◽  
Anshu Bhardwaj
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Chemical Space ◽  
Pharmacophore Model ◽  
Model Systems ◽  
Receptor Interaction ◽  
Hybrid Molecules ◽  
Wide Range ◽  
Binding Pockets ◽  
Pharmacophore Models

Antimicrobial resistance (AMR) is one of the most serious global public health threats as it compromises the successful treatment of deadly infectious diseases like tuberculosis. New therapeutics are constantly needed but it takes a long time and is expensive to explore new biochemical space. One way to address this issue is to repurpose the validated targets and identify novel chemotypes that can simultaneously bind to multiple binding pockets of these targets as a new lead generation strategy. This study reports such a strategy, dynamic hybrid pharmacophore model (DHPM), which represents the combined interaction features of different binding pockets contrary to the conventional approaches, where pharmacophore models are generated from single binding sites. We have considered Mtb-DapB, a validated mycobacterial drug target, as our model system to explore the effectiveness of DHPMs to screen novel unexplored compounds. Mtb-DapB has a cofactor binding site (CBS) and an adjacent substrate binding site (SBS). Four different model systems of Mtb-DapB were designed where, either NADPH/NADH occupies CBS in presence/absence of an inhibitor 2, 6-PDC in the adjacent SBS. Two more model systems were designed, where 2, 6-PDC was linked to NADPH and NADH to form hybrid molecules. The six model systems were subjected to 200 ns molecular dynamics simulations and trajectories were analyzed to identify stable ligand-receptor interaction features. Based on these interactions, conventional pharmacophore models (CPM) were generated from the individual binding sites while DHPMs were created from hybrid-molecules occupying both binding sites. A huge library of 1,563,764 publicly available molecules were screened by CPMs and DHPMs. The screened hits obtained from both types of models were compared based on their Hashed binary molecular fingerprints and 4-point pharmacophore fingerprints using Tanimoto, Cosine, Dice and Tversky similarity matrices. Molecules screened by DHPM exhibited significant structural diversity, better binding strength and drug like properties as compared to the compounds screened by CPMs indicating the efficiency of DHPM to explore new chemical space for anti-TB drug discovery. The idea of DHPM can be applied for a wide range of mycobacterial or other pathogen targets to venture into unexplored chemical space.

An Automated Method for the Determination of Sulfonamides in Plasma

1965 ◽  
Vol 11 (12) ◽  
pp. 1045-1050 ◽  
Author(s):  
H B Falk ◽  
R G Kelly
Keyword(s):  
Protein Binding ◽  
Automated Method

Abstract An automated adaptation of the Bratton-Marshall procedure for sulfonamides has been developed. As sulfonamides exhibit varying degrees of protein binding, application of the method to plasma is dependent upon release of these compounds prior to automated dialysis. This release is effected by the acidification of the sample. The results obtained with and without this preliminary acidification are discussed.

scholarly journals RsiteDB: a database of protein binding pockets that interact with RNA nucleotide bases

2009 ◽  
Vol 37 (Database) ◽  
pp. D369-D373 ◽  
Author(s):  
A. Shulman-Peleg ◽  
R. Nussinov ◽  
H. J. Wolfson
Keyword(s):  
Protein Binding ◽  
Binding Pockets ◽  
Nucleotide Bases

Incorporation of side chain flexibility into protein binding pockets using MTflex

2016 ◽  
Vol 24 (20) ◽  
pp. 4978-4987 ◽  
Author(s):  
Nupur Bansal ◽  
Zheng Zheng ◽  
Kenneth M. Merz
Keyword(s):  
Protein Binding ◽  
Side Chain ◽  
Chain Flexibility ◽  
Binding Pockets

scholarly journals Computational Analysis of HIV-1 Protease Protein Binding Pockets

2010 ◽  
Vol 50 (10) ◽  
pp. 1759-1771 ◽  
Author(s):  
Gene M. Ko ◽  
A. Srinivas Reddy ◽  
Sunil Kumar ◽  
Barbara A. Bailey ◽  
Rajni Garg
Keyword(s):  
Protein Binding ◽  
Computational Analysis ◽  
Binding Pockets ◽  
Hiv 1

scholarly journals Free enthalpies of replacing water molecules in protein binding pockets

2012 ◽  
Vol 26 (12) ◽  
pp. 1293-1309 ◽  
Author(s):  
Sereina Riniker ◽  
Luzi J. Barandun ◽  
François Diederich ◽  
Oliver Krämer ◽  
Andreas Steffen ◽  
...  
Keyword(s):  
Protein Binding ◽  
Water Molecules ◽  
Binding Pockets

A fully automated, continuous-flow radioimmunoassay for methotrexate.

1980 ◽  
Vol 26 (1) ◽  
pp. 97-100 ◽  
Author(s):  
R Kamel ◽  
J Landon ◽  
G C Forrest
Keyword(s):  
Electromagnetic Field ◽  
Protein Binding ◽  
Continuous Flow ◽  
Binding Assay ◽  
Solid Phase ◽  
Separation Technique ◽  
Automated Method ◽  
Protein Binding Assay ◽  
Competitive Protein Binding Assay ◽  
Competitive Protein Binding

Abstract We describe a fully automated continuous-flow radioimmunoassay for methotrexate. [125I]Histamine-labeled methotrexate was used as tracer. Anti-methotrexate serum was coupled to a magnetizable solid-phase and the bound and free fractions were separated with an electromagnetic field. The assay is precise (CV less than 2.5%) and rapid (30 samples per hour), incubation volume is small (about 160 micro L), and incubation brief (10 min). The accurate timing inherent in the system obviates the need to attain equilibrium, so that assay of each sample takes only 15 min. The assay is sensitive (1--100 microgram/L). There is no significant carryover between samples of high and low concentration. Results by the automated method correlated well with those by both a manual assay in which the same reagents and separation technique are used (r - 0.99) and a competitive protein-binding assay (r = 0.96).

scholarly journals TRAPP webserver: predicting protein binding site flexibility and detecting transient binding pockets

2017 ◽  
Vol 45 (W1) ◽  
pp. W325-W330 ◽  
Author(s):  
Antonia Stank ◽  
Daria B. Kokh ◽  
Max Horn ◽  
Elena Sizikova ◽  
Rebecca Neil ◽  
...  
Keyword(s):  
Protein Binding ◽  
Binding Site ◽  
Protein Binding Site ◽  
Binding Pockets

Large-Scale Mining for Similar Protein Binding Pockets: With RAPMAD Retrieval on the Fly Becomes Real

2014 ◽  
Vol 55 (1) ◽  
pp. 165-179 ◽  
Author(s):  
Timo Krotzky ◽  
Christian Grunwald ◽  
Ute Egerland ◽  
Gerhard Klebe
Keyword(s):  
Protein Binding ◽  
Large Scale ◽  
Similar Protein ◽  
Binding Pockets

scholarly journals Hybrid dynamic pharmacophore models as effective tools to identify novel chemotypes for anti-TB inhibitor design: A case study with Mtb-DapB

2020 ◽  
Author(s):  
Chinmayee Choudhury ◽  
Anshu Bhardwaj
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Chemical Space ◽  
Pharmacophore Model ◽  
Model Systems ◽  
Receptor Interaction ◽  
Hybrid Molecules ◽  
Wide Range ◽  
Binding Pockets ◽  
Pharmacophore Models

AbstractAntimicrobial resistance (AMR) is one of the most serious global public health threats as it compromises the successful treatment of deadly infectious diseases like tuberculosis. New therapeutics are constantly needed but it takes a long time and is expensive to explore new biochemical space. One way to address this issue is to repurpose the validated targets and identify novel chemotypes that can simultaneously bind to multiple binding pockets of these targets as a new lead generation strategy. This study reports such a strategy, dynamic hybrid pharmacophore model (DHPM), which represents the combined interaction features of different binding pockets contrary to the conventional approaches, where pharmacophore models are generated from single binding sites. We have considered Mtb-DapB, a validated mycobacterial drug target, as our model system to explore the effectiveness of DHPMs to screen novel unexplored compounds. Mtb-DapB has a cofactor binding site (CBS) and an adjacent substrate binding site (SBS). Four different model systems of Mtb-DapB were designed where, either NADPH/NADH occupies CBS in presence/absence of an inhibitor 2, 6-PDC in the adjacent SBS. Two more model systems were designed, where 2, 6-PDC was linked to NADPH and NADH to form hybrid molecules. The six model systems were subjected to 200ns molecular dynamics simulations and trajectories were analyzed to identify stable ligand-receptor interaction features. Based on these interactions, conventional pharmacophore models (CPM) were generated from the individual binding sites while DHPMs were created from hybrid-molecules occupying both binding sites. A huge library of 15, 63,764 publicly available molecules were screened by CPMs and DHPMs. The screened hits obtained from both types of models were compared based on their Hashed binary molecular fingerprints and 4-point pharmacophore fingerprints using Tanimoto, Cosine, Dice and Tversky similarity matrices. Molecules screened by DHPM exhibited significant structural diversity, better binding strength and drug like properties as compared to the compounds screened by CPMs indicating the efficiency of DHPM to explore new chemical space for anti-TB drug discovery. The idea of DHPM can be applied for a wide range of mycobacterial or other pathogen targets to venture into unexplored chemical space.

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