Understanding the role of short- and long-range intermolecular interactions in novel computational drug discovery

Abstract

Introduction: Understanding the interactions between functional groups, ligands, molecular fragments, and whole molecules is critical in modern drug discovery. Key to this endeavor is the theoretical development of the fundamental inter-particle forces at play and their implementation in numerous software packages that allow the calculation of interaction energies at varying levels of theory ranging from the entirely classical at one extreme to the fully quantum mechanical at the other.

Areas covered: In this review, the authors consider the concept of an intermolecular potential energy function and its separation into short- and long-range regions. This is followed by a summary of the perturbation theory calculation of the electrostatic, induction, and dispersion energy shifts by expanding the charge distribution in terms of source multipole moments. Next, the authors outline the construction of a typical molecular force field and its parameterization; they also discuss the fundamental background of molecular dynamics (MD) simulations, their implementation in several well-known software packages and their deployment in modern computational drug discovery, including recent work with Artificial Intelligence and Machine Learning techniques. Papers cited by SSC were the result of a literature search conducted using PubMed and Google Scholar during Jan-July 2025 as well as from the authors' personal literature stock.

Expert opinion: While the underlying quantum mechanical theory of intermolecular forces is well-known, their accurate and reliable calculation for an ever-growing variety of increasingly complex systems mirrors the advances in computational hardware on which such simulations are performed. Coupled with emerging machine learning techniques, this allows for the rapid and efficient computer-aided discovery of potential new drug candidates, in the process revolutionizing research and development in both academia and industry.

Keywords: Intermolecular potential; computational drug discovery; force fields; machine learning (ML); molecular docking; molecular dynamics (MD) simulations; parameterization; short- and long-range forces.