Understanding the impact of binding free energy and kinetics calculations in modern drug discovery.
Expert Opin Drug Discov
; 19(6): 671-682, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38722032
ABSTRACT
INTRODUCTION:
For rational drug design, it is crucial to understand the receptor-drug binding processes and mechanisms. A new era for the use of computer simulations in predicting drug-receptor interactions at an atomic level has begun with remarkable advances in supercomputing and methodological breakthroughs. AREAS COVERED End-point free energy calculation methods such as Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA) or Molecular-Mechanics/Generalized Born Surface Area (MM/GBSA), free energy perturbation (FEP), and thermodynamic integration (TI) are commonly used for binding free energy calculations in drug discovery. In addition, kinetic dissociation and association rate constants (koff and kon) play critical roles in the function of drugs. Nowadays, Molecular Dynamics (MD) and enhanced sampling simulations are increasingly being used in drug discovery. Here, the authors provide a review of the computational techniques used in drug binding free energy and kinetics calculations. EXPERT OPINION The applications of computational methods in drug discovery and design are expanding, thanks to improved predictions of the binding free energy and kinetic rates of drug molecules. Recent microsecond-timescale enhanced sampling simulations have made it possible to accurately capture repetitive ligand binding and dissociation, facilitating more efficient and accurate calculations of ligand binding free energy and kinetics.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Termodinâmica
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Desenho de Fármacos
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Descoberta de Drogas
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Simulação de Dinâmica Molecular
Limite:
Humans
Idioma:
En
Revista:
Expert Opin Drug Discov
Ano de publicação:
2024
Tipo de documento:
Article