Understanding the impact of binding free energy and kinetics calculations in modern drug discovery.

IF 6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Expert Opinion on Drug Discovery Pub Date : 2024-06-01 Epub Date: 2024-05-09 DOI:10.1080/17460441.2024.2349149
Victor A Adediwura, Kushal Koirala, Hung N Do, Jinan Wang, Yinglong Miao
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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.

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了解结合自由能和动力学计算对现代药物发现的影响。
导言:要进行合理的药物设计,了解受体与药物的结合过程和机制至关重要。随着超级计算技术的显著进步和方法上的突破,利用计算机模拟在原子水平上预测药物与受体相互作用的新时代已经来临:端点自由能计算方法,如分子力学/泊松玻尔兹曼表面积(MM/PBSA)或分子力学/广义玻恩表面积(MM/GBSA)、自由能扰动(FEP)和热力学积分(TI),常用于药物发现中的结合自由能计算。此外,动力学解离和结合速率常数(koff 和 kon)对药物的功能起着至关重要的作用。如今,分子动力学(MD)和增强采样模拟正越来越多地用于药物发现。在此,作者对用于药物结合自由能和动力学计算的计算技术进行了综述:由于对药物分子结合自由能和动力学速率的预测得到了改进,计算方法在药物发现和设计中的应用正在不断扩大。最近的微秒级增强采样模拟使准确捕捉配体的重复结合和解离成为可能,从而有助于更高效、更准确地计算配体结合自由能和动力学。
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来源期刊
CiteScore
10.20
自引率
1.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Expert Opinion on Drug Discovery (ISSN 1746-0441 [print], 1746-045X [electronic]) is a MEDLINE-indexed, peer-reviewed, international journal publishing review articles on novel technologies involved in the drug discovery process, leading to new leads and reduced attrition rates. Each article is structured to incorporate the author’s own expert opinion on the scope for future development. The Editors welcome: Reviews covering chemoinformatics; bioinformatics; assay development; novel screening technologies; in vitro/in vivo models; structure-based drug design; systems biology Drug Case Histories examining the steps involved in the preclinical and clinical development of a particular drug The audience consists of scientists and managers in the healthcare and pharmaceutical industry, academic pharmaceutical scientists and other closely related professionals looking to enhance the success of their drug candidates through optimisation at the preclinical level.
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