PDBrt: A free database of complexes with measured drug-target residence time

Background: Difficulties in translating the in vitro potency determined by cellular assays into in vivo efficacy in living organisms complicates the design and development of drugs. However, the residence time of a drug in its molecular target is becoming a key parameter in the design and optimization of new drugs, as recent studies show that residence time can reliably predict drug efficacy in vivo. Experimental approaches to binding kinetics and target ligand complex solutions are currently available, but known bioinformatics databases do not usually report information about the ligand residence time in its molecular target. Methods: To extend existing databases we developed the Protein Data Bank (PDB) residence time database (PDBrt) which reports drug residence time. The database is implemented as an open access web-based tool. The front end uses Bootstrap with Hypertext Markup Language (HTML), jQuery for the interface and 3Dmol.js to visualize the complexes. The server-side code uses Python web application framework, Django Rest Framework and backend database PostgreSQL. Results: The PDBrt database is a free, non-commercial repository for 3D protein-ligand complex data, including the measured ligand residence time inside the binding pocket of the specific biological macromolecules as deposited in The Protein Data Bank. The PDBrt database contains information about both the protein and the ligand separately, as well as the protein-ligand complex, binding kinetics, and time of the ligand residence inside the protein binding site. Availability: https://pdbrt.polsl.pl

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Kinetics of Drug Binding and Residence Time

Annual Review of Physical Chemistry ◽

10.1146/annurev-physchem-042018-052340 ◽

2019 ◽

Vol 70 (1) ◽

pp. 143-171 ◽

Cited By ~ 22

Author(s):

Mattia Bernetti ◽

Matteo Masetti ◽

Walter Rocchia ◽

Andrea Cavalli

Keyword(s):

Computational Methods ◽

Residence Time ◽

Drug Target ◽

Early Stage ◽

Kinetic Constant ◽

Theoretical Background ◽

Drug Binding ◽

Binding Kinetics ◽

Kinetics Of

The kinetics of drug binding and unbinding is assuming an increasingly crucial role in the long, costly process of bringing a new medicine to patients. For example, the time a drug spends in contact with its biological target is known as residence time (the inverse of the kinetic constant of the drug-target unbinding, 1/ koff). Recent reports suggest that residence time could predict drug efficacy in vivo, perhaps even more effectively than conventional thermodynamic parameters (free energy, enthalpy, entropy). There are many experimental and computational methods for predicting drug-target residence time at an early stage of drug discovery programs. Here, we review and discuss the methodological approaches to estimating drug binding kinetics and residence time. We first introduce the theoretical background of drug binding kinetics from a physicochemical standpoint. We then analyze the recent literature in the field, starting from the experimental methodologies and applications thereof and moving to theoretical and computational approaches to the kinetics of drug binding and unbinding. We acknowledge the central role of molecular dynamics and related methods, which comprise a great number of the computational methods and applications reviewed here. However, we also consider kinetic Monte Carlo. We conclude with the outlook that drug (un)binding kinetics may soon become a go/no go step in the discovery and development of new medicines.

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PatternQuery: web application for fast detection of biomacromolecular structural patterns in the entire Protein Data Bank

Nucleic Acids Research ◽

10.1093/nar/gkv561 ◽

2015 ◽

Vol 43 (W1) ◽

pp. W383-W388 ◽

Cited By ~ 16

Author(s):

David Sehnal ◽

Lukáš Pravda ◽

Radka Svobodová Vařeková ◽

Crina-Maria Ionescu ◽

Jaroslav Koča

Keyword(s):

Protein Data Bank ◽

Web Application ◽

Data Bank ◽

Structural Patterns ◽

Fast Detection

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GeoMine: interactive pattern mining of protein–ligand interfaces in the Protein Data Bank

Bioinformatics ◽

10.1093/bioinformatics/btaa693 ◽

2020 ◽

Author(s):

Konrad Diedrich ◽

Joel Graef ◽

Katrin Schöning-Stierand ◽

Matthias Rarey

Keyword(s):

Protein Data Bank ◽

Web Application ◽

Pattern Mining ◽

Structural Data ◽

Data Bank ◽

Supplementary Information ◽

User Friendliness ◽

Iterative Search ◽

Potential Applications ◽

Query Generation

Abstract Summary The searching of user-defined 3D queries in molecular interfaces is a computationally challenging problem that is not satisfactorily solved so far. Most of the few existing tools focused on that purpose are desktop based and not openly available. Besides that, they show a lack of query versatility, search efficiency and user-friendliness. We address this issue with GeoMine, a publicly available web application that provides textual, numerical and geometrical search functionality for protein–ligand binding sites derived from structural data contained in the Protein Data Bank (PDB). The query generation is supported by a 3D representation of a start structure that provides interactively selectable elements like atoms, bonds and interactions. GeoMine gives full control over geometric variability in the query while performing a deterministic, precise search. Reasonably selective queries are processed on the entire set of protein–ligand complexes in the PDB within a few minutes. GeoMine offers an interactive and iterative search process of successive result analyses and query adaptations. From the numerous potential applications, we picked two from the field of side-effect analyze showcasing the usefulness of GeoMine. Availability and implementation GeoMine is part of the ProteinsPlus web application suite and freely available at https://proteins.plus. Supplementary information Supplementary data are available at Bioinformatics online.

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In silico prospection of antineoplastic molecules from the Artemisia annua species

Revista Brasileira Militar de Ciências ◽

10.36414/rbmc.v7i19.105 ◽

2021 ◽

Vol 7 (19) ◽

Author(s):

Isabela Sacienti Lavezo ◽

Juracy Cirino de Souza Neto ◽

Túlio Nunes Pinto ◽

Leonardo Luiz Borges

Keyword(s):

In Silico ◽

Artemisia Annua ◽

Biological Effects ◽

Low Cost ◽

Target Prediction ◽

Molecular Target ◽

New Drugs ◽

Antineoplastic Activity

Lung cancer kills the most men and the second that kills the most women (behind only breast cancer). The in silico study makes it possible to search for new drugs at low cost, with a greater possibility of rapid manufacturing and a lower future cost for their manufacture. The objective of this study was to analyze an antineoplastic activity of the compounds of Artemisia annua to obtain an active substance that can reach the molecular target of the cancer cells. Compounds with antineoplastic effects were selected using Scielo, PubMed, and ScienceDirect platforms. Afterward, the first screening of compound compounds was performed with a high ability to predict biological and pharmacological activity through the PASS Prediction, Pubchem, and Swiss ADME platforms. After the current screening, we determined the toxicological and molecular target prediction by the Portox II and Swiss Target Prediction platforms. As a final part, molecular docking and redocking were performed for a compound using the PDB server and the GOLD Suite 5.7.0 program. For another, we completed the pharmacophoric mapping using the Binding DB and PharmaGist database. The compounds scopoletin and caffeic acid were the most promising structures in silico models capable of interacting with EGFR (epidermal growth factor) and MM-9 (metalloproteinase type 9), respectively. The results obtained that these structures are promising to be tested in in vitro and in vivo tests about the antineoplastic activity. In addition, in silico analyses help to understand the biological effects of A. annua extracts regarding antineoplastic evidence.

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soaPDB: a web application for searching the Protein Data Bank, organizing results, and receiving automatic email alerts

Nucleic Acids Research ◽

10.1093/nar/gkn270 ◽

2008 ◽

Vol 36 (Web Server) ◽

pp. W252-W254 ◽

Cited By ~ 1

Author(s):

C. A. Lesburg ◽

J. S. Duca

Keyword(s):

Protein Data Bank ◽

Web Application ◽

Data Bank

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POTENSI SENYAWA BIOAKTIF TANAMAN KELOR PENGHAMBAT INTERAKSI ANGIOTENSIN-CONVERTING ENZYME 2 PADA SINDROMA SARS-COV-2

Jurnal Bioteknologi & Biosains Indonesia (JBBI) ◽

10.29122/jbbi.v7i2.4156 ◽

2020 ◽

Vol 7 (2) ◽

pp. 259-270

Author(s):

Maharani Pertiwi Koentjoro ◽

Adyan Donastin ◽

Endry Nugroho Prasetyo

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Protein Data Bank ◽

Active Sites ◽

Moringa Oleifera ◽

Data Bank ◽

Converting Enzyme ◽

Ligand Complex ◽

Angiotensin Converting Enzyme 2 ◽

Pubchem Database

The Potential of Moringa oleifera Bioactive Compounds for Inhibiting Angiotensin-Converting Enzyme 2 Interaction in SARS-Cov-2 Syndrome Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease (COVID-19) is a threat to human health. This infection is determined by the interaction of the spike S1 domain protein with angiotensin-converting enzyme 2 (ACE2) in the epithelial cells of the respiratory tract, especially the lungs. ACE2 inhibition is an important target in controlling COVID-19. Flavonoids of medicinal plants, are known to interfere with ACE (ACE2 homologous). Therefore, this study aims to explore the ability of apiin, epicatechin, and hesperetin from Moringa oleifera in interacting with the ACE2 using MOE 2008.10. The ligand molecules were prepared from PubChem database. The ACE2 protein was retrieved from Protein Data Bank (ID 1R4L) and analyzed for the active sites. Analysis of docking scores and hydrogen bonds of ACE2-ligand complex and active site showed that the affinity of flavonoids can be ranked as hesperetin > epicatechin > apiin > C19H23Cl2N3O4. The results provided computational information that apiin, epicatechin, and hesperetin have the potential to prevent COVID-19 infection. The prediction of activity spectra for substances (PASS) score showed the ligand displays antiviral activity. Infeksi severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pada pandemi coronavirus disease 2019 (COVID-19) menjadi ancaman dunia kesehatan saat ini. Infeksi SARS-CoV-2 ditentukan oleh interaksi protein spike envelope S1 domain dengan reseptor angiotensin-converting enzyme 2 (ACE2) yang diekspresikan pada sel epitel saluran pernafasan terutama paru-paru. Mekanisme penghambatan ACE2 menjadi target penting dalam pengendalian COVID-19. Senyawa bioaktif tanaman obat, seperti flavonoid diketahui mampu mengganggu fungsi banyak makromolekul termasuk ACE (homolog dengan ACE2). Penelitian ini bertujuan mengeksplorasi kemampuan senyawa apiin, epicatechin, dan hesperetin dari Moringa oleifera dalam berinteraksi dengan sisi aktif ACE2 menggunakan metode penambatan molekul. Studi dilakukan dengan preparasi struktur molekul ligan dari PubChem database dan diolah dengan MOE 2008.10. Selanjutnya, data protein ACE2 (Protein Data Bank ID 1R4L) dianalisis sisi aktifnya untuk mengetahui lokasi penambatan ligan senyawa. Analisis skor docking dan ikatan hydrogen komplek ligan dan sisi aktif ACE2 menunjukkan bahwa afinitas flavonoid dapat diperingkatkan sebagai afinitas hesperetin > epicatechin > apiin > C19H23Cl2N3O4. Ketiga ligan senyawa yang terkandung dalam M. oleifera secara in silico mampu mengikat sisi aktif ACE2, sehingga berpotensi mencegah infeksi COVID-19. Skor PASS (prediction of activity spectra for substances) menunjukkan aktivitas biologis ligan yang menyerupai antiviral.

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El papel de la vitamina d en la respuesta inmune y en las enfermedades alérgicas

Revista Ciencias Biomédicas ◽

10.32997/rcb-2015-2960 ◽

2020 ◽

Vol 6 (2) ◽

pp. 319-332

Author(s):

Catherine Meza Torres ◽

Javier Marrugo Cano

Keyword(s):

Protein Data Bank ◽

Data Bank ◽

Vitamina D ◽

El Sistema

Introducción: la vitamina D es una de las moléculas más pleiotrópicas. Juega un papelimportante en el metabolismo del calcio, en la salud pulmonar y en el sistema inmune.En estudios epidemiológicos se ha relacionado la insuficiencia de esta vitamina con elasma y la dermatitis atópica. Así mismo, algunos estudios genéticos que incluyen hastael rastreo genómico han reportado asociación entre el receptor de la vitamina D (VDR)y el asma.Objetivo: identificar el papel de la vitamina D en la respuesta inmune y en lasenfermedades alérgicas.Metodología: se realizó una búsqueda electrónica en las bases de datos PubMed,ScienceDirect, Protein data Bank, NCBI, Blackwell Synergy Wiley Online Library.Resultados: se selecionaron 120 articulos para la revision y se escogieron 76 articuloscompletos y dos resúmenes de nuestro grupo.Conclusión: estudios epidemiológicos y de genética han relacionado a la vitamina Dy su receptor (VDR) con el desarrollo de las enfermedades alérgicas. Esta evidencia esextensa y en ocasiones contradictoria, la cual se podría explicar por el reclutamientodiferencial de coactivadores del complejo VD-VDR-RXR. Sin embargo, la mayoría de losestudios experimentales in vitro e in vivo demuestran que la vitamina D ejerce un efectomodulador sobre diversos tipos de células del sistema inmune innato y adaptativo, asícomo sobre las células involucradas en la respuesta inmune del tipo Th1, Th2, Treg yTh17. Se concluye que esta vitamina juega un papel fundamental sobre las respuestasinmunes innatas y adaptativas, así como en el desarrollo de las enfermedades alérgicas.Rev.cienc.biomed. 2015;6(2):319-332

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AVALIAÇÃO DAS POSSÍVEIS INTERAÇÕES POR DOCKING MOLECULAR DOS FITOCONSTITUINTES DO ÓLEO ESSENCIAL DE ROSMARINUS OFFICINALIS L. EM ENZIMAS DE CANDIDA SPP

Revista interdisciplinar em saúde ◽

10.35621/23587490.v7.n1.p1461-1479 ◽

2020 ◽

Vol 7 (Único) ◽

pp. 1461-1479

Author(s):

Pedro Thiago Ramalho de Figueiredo ◽

Laísa Vilar Cordeiro ◽

Thamara Rodrigues de Melo ◽

Giulian César da Silva Sá ◽

Aleson Pereira de Sousa

Keyword(s):

Protein Data Bank ◽

Data Bank ◽

Rosmarinus Officinalis ◽

Candida Spp ◽

Molegro Virtual Docker ◽

Rosmarinus Officinalis L

A grande biodiversidade de plantas medicinais encontradas no Brasil apresenta grande importância para a medicina popular, pois diversas espécies de plantas medicinais são utilizadas para o tratamento e cura de doenças. Dessa maneira, as plantas medicinais apresentam potencial na descoberta e desenvolvimento de novos fármacos. Para auxiliar nos estudos de desenvolvimentos de novos fármacos, as técnicas quimioinformáticas se tornaram uma aliada dos pesquisadores ao reduzir tempo e gastos durante este processo. Neste sentido, o óleo essencial de Rosmarinus officinalis L. (Lamiaceae) é conhecida popularmente como alecrim-de-jardim, alecrim-de-cheiro e apresenta importante atividade antifúngica sendo um grande fator para a descoberta de novas substâncias químicas com potencial antifúngico. Este trabalho tem como objetivo, analisar por docking molecular as interações de metabólitos secundários encontrados no óleo essencial de Rosmarinus officinalis em diferentes enzimas de Candida spp. Os metabólitos secundários do óleo essencial de Rosmarinus officinalis foram obtidos da literatura, as enzimas foram adquiridas do Protein Data Bank sob código 5TZ1 (14α-lanosterol-demetilase) e 1EQC (exo-beta-(1,3)-glucanase) com seus respectivos ligantes. O docking molecular foi realizado utilizando o software Molegro Virtual Docker. Após análise do docking molecular, as substâncias tiveram melhor afinidade pela enzima 14α- lanosterol-demetilase, destacando o clovenol que apresentou energia de ligação semelhante ao inibidor cocristalizado. Com esse estudo podemos mostrar a importância do docking para a identificar possíveis locais de atuação de metabólitos secundários e sugerir que as substâncias químicas do óleo essencial podem atuar a nível de membrana celular sendo necessários estudos in vivo e in vitro para confirmação.

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