Prediction of protein-ligand binding affinity by free energy simulations: assumptions, pitfalls and expectations

Julien Michel, Jonathan W. Essex

Research output: Contribution to journalArticlepeer-review


Many limitations of current computer-aided drug design arise from the difficulty of reliably predicting the binding affinity of a small molecule to a biological target. There is thus a strong interest in novel computational methodologies that claim predictions of greater accuracy than current scoring functions, and at a throughput compatible with the rapid pace of drug discovery in the pharmaceutical industry. Notably, computational methodologies firmly rooted in statistical thermodynamics have received particular attention in recent years. Yet free energy calculations can be daunting to learn for a novice user because of numerous technical issues and various approaches advocated by experts in the field. The purpose of this article is to provide an overview of the current capabilities of free energy calculations and to discuss the applicability of this technology to drug discovery.

Original languageEnglish
Pages (from-to)639-658
Number of pages20
JournalJournal of computer-Aided molecular design
Issue number8
Publication statusPublished - Aug 2010

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