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PERSPECTIVE

The role of NMR in leveraging dynamics and entropy in drug design Abhinav Dubey1,4 · Koh Takeuchi2 · Mikhail Reibarkh3 · Haribabu Arthanari1,4  Received: 21 April 2020 / Accepted: 11 July 2020 © Springer Nature B.V. 2020

Abstract Nuclear magnetic resonance (NMR) spectroscopy has contributed to structure-based drug development (SBDD) in a unique way compared to the other biophysical methods. The potency of a ligand binding to a protein is dictated by the binding free energy, which is an intricate interplay between entropy and enthalpy. In addition to providing the atomic resolution structural information, NMR can help to identify protein–ligand interactions that potentially contribute to the enthalpic component of the free energy. NMR can also illuminate dynamic aspects of the interaction, which correspond to the entropic term of the free energy. The ability of NMR to access both terms in the free energy equation stems from the suite of experiments developed to shed light on various aspects that contribute to both entropy and enthalpy, deepening our understanding of the biological function of macromolecules and assisting to target them in physiological conditions. Here we provide a brief account of the contribution of NMR to SBDD, highlighting hallmark examples and discussing the challenges that demand further method development. In the era of integrated biology, the unique ability of NMR to directly ascertain structural and dynamical aspects of macromolecule and monitor changes in these properties upon engaging a ligand can be combined with computational and other structural and biophysical methods to provide a more complete picture of the energetics of drug engagement with the target. Such efforts can be used to engineer better drugs. Keywords  NMR · Therapeutics · Drug discovery · Thermodynamics · Entropy · Enthalpy · Free energy · Protein–ligand interactions

Introduction

Abhinav Dubey and Koh Takeuchi have contributed equally to this work. * Koh Takeuchi koh‑[email protected] * Haribabu Arthanari [email protected] 1



Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA

2



Cellular and Molecular Biotechnology Research Institute & Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135‑0064, Japan

3

Analytical Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA

4

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA



Much like a sculptor transforms a stone into a masterpiece using her artistic tools, a medicinal chemist transforms a molecule in the laboratory setting to a drug in the clinical setting guided by the laws of thermodynamics. Thermodynamic parameters are an important measure used to improve the specificity and affinity of a molecule to given target. Medicinal chemists use a host of biophysical techniques to derive these parameters at different stages of the drug discovery process