Drug development is a remarkably complex subject, with potency and
specificity being the desired traits in the early stages of research. Yet, these need
careful thought and rational design, which has led to the inclusion of multidisciplinary
efforts and non-chemistry methods in the ever-changing landscape of medicinal
chemistry. Computational approximation of protein-ligand interactions is the main goal
of the so-called structure-based methods. Over the years, there has been a notable
improvement in the predictive power of approaches like molecular force fields.
Mainstream applications of these include molecular docking, a well-known method for
high-throughput virtual screening. Still, even with notable success cases, the search for
accurate and efficient methods for free energy estimation remains a major goal in the
field. Recently, with the advent of technology, more exhaustive simulations are
possible in a reasonable time. Herein, we discuss free energy predictions and
applications of perturbation theory, with emphasis on their role in molecular design and
drug discovery. Our aim is to provide a concise but comprehensive view of current
trends, best practices, and overall perspectives in this maturing field of computational
chemistry.
Keywords: Alchemistry, Computer-aided Drug Design, Free Energy Methods and Simulation.
