A mathematical formalism to quantify drug-target residence time
Ortiz, Antonio J. (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Romero i Sànchez, David (Centre de Recerca Matemàtica)
Guillamon, Antoni (Centre de Recerca Matemàtica)
Giraldo, Jesús (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)
Universitat Autònoma de Barcelona. Institut de Neurociències

Date:	2025
Description:	22 pàg.
Abstract:	Despite drug-target residence time (RT) is a key topic in binding kinetics, little information exists on its theoretical quantification. The two most frequent mathematical expressions found in the literature correspond to two particular and simple pharmacological cases: the binary ligand-receptor complex and the induction-fit model. In this article, we propose a mathematical formalism to obtain an expression of RT that can be of general applicability. RT is calculated from the system of ordinary differential equations (ODE) obtained by applying the Law of Mass Action to the selected chemical process. Then, a subsystem is constructed by defining which chemical species are of interest and omitting their global formation processes. RT maintains its accepted definition of 1/koff, where koff is here defined as the absolute value of the smallest-modulus eigenvalue of the subsystem. The proposed procedure is successfully used to derive RT for a wide variety of pharmacological cases. In particular, the theoretical expressions of RT obtained for binary ligand-receptor binding and induction-fit coincide with those previously found in the literature. An extension of the RT pharmacological framework is proposed by including the concept of relaxation time (RXT), which involves pharmacological conditions associated with receptor activation rather than receptor binding. To conclude, the herein presented formalism for RT and RXT provides a mathematical framework that can be of general applicability in many pharmacological systems. It is expected that the procedure may be helpful in different pharmacological areas such as binding kinetics, PK/PD and enzymology.
Grants:	European Commission 848068 Agencia Estatal de Investigación PID2020-119136RB-I00 Agencia Estatal de Investigación PID2021-122954NB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01039
Note:	Altres ajuts: acords transformatius de la UAB
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Residence time ; Binding kinetics ; Receptor heterodimerization ; Conformational selection ; Induction fit ; Constitutive receptor activity
Published in:	Biochemical pharmacology, Vol. 239, ISSN 1873-2968

DOI: 10.1016/j.bcp.2025.117037
PMID: 40516761

22 p, 2.8 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Parc Taulí Research and Innovation Institute (I3PT
Articles > Research articles
Articles > Published articles