Abstract

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

Highlights

  • Current knowledge allowing for the determination of the effectiveness of small molecules in vivo is limited

  • Traditional computational approaches take into account only the equilibrium affinity of the drug for its molecular target (e.g., Ki); the concept of residence time takes into account conformational dynamics of molecules, which can have a significant effect on the binding and dissociation of the drug (Copeland et al, 2006; Tummino & Copeland, 2008)

  • The RESTful application programming interface (API) with the Django Rest Framework (v2.2.20) and a backend PostgreSQL (v12) database running on a Nginx (v1.21.3) web server has been developed to represent the output of a query as a user-friendly web page generated in Bootstrap (v3.3.7) with Hypertext Markup Language (HTML), Cascading Style Sheets (CSS) and jQuery (v3.5.1) to report the results

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Summary

SOFTWARE TOOL ARTICLE

PDBrt: A free database of complexes with measured drugtarget residence time [version 1; peer review: awaiting peer review].

Introduction
Implementation PDBrt database design and structure
PDBrt database management system
Binding kinetics data acquisition and extraction
Structural data acquisition
PDBrt data content
PDBrt database availability and updates
PDBrt database architecture
PDBrt database model
Full Text
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