Enhanced Configurational Sampling in Binding Free-Energy Calculations

Essex

2008

J. Med. Chem.

Self Cite

The identification of lead molecules using computational modeling often relies on approximate, highthroughput approaches, of limited accuracy. We show here that, with a methodology we recently developed, it is possible to predict the relative binding free energies of structurally diverse ligands of the estrogen receptor-R using a rigorous statistical thermodynamics approach. Predictions obtained from the simulations with an explicit solvation model are in good qualitative agreement with experimental data, while simulations with implicit solvent models or rank ordering by empirical scoring functions yield predictions of lower quality. In addition, it is shown that free energy techniques can be used to select the most likely binding mode from a set of possible orientations generated by a docking program. It is suggested that the free energy techniques outlined in this study can be used to rank-order, by potency, structurally diverse compounds identified by virtual screening, de novo design or scaffold hopping programs.

Section: Methodsmentioning

confidence: 99%

Hit Identification and Binding Mode Predictions by Rigorous Free Energy Simulations

Essex

2008

J. Med. Chem.

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“…49 Utilising the method with replica exchange thermodynamic integration (RETI), 50,51 the study focussed on understanding whether the binding affinity of a water molecule was related to its propensity to be displaced.…”

Section: Studies By Setny Baron and Mccammonmentioning

confidence: 99%

Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Bodnarchuk

Viner

et al. 2014

J. Chem. Inf. Model.

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Water molecules are commonplace in protein binding pockets, where they can typically form a complex between the protein and a ligand or become displaced upon ligand binding.As a result, it is often of great interest to establish both the binding free energy and location of such molecules. Several approaches to predicting the location and affinity of water molecules to proteins have been proposed and utilized in the literature, although it is often unclear which method should be used under what circumstances. We report here a comparison between three such methodologies; Just Add Water Molecules (JAWS), Grand Canonical Monte Carlo (GCMC) and double-decoupling, in the hope of understanding the advantages and limitations of each method when applied to enclosed binding sites. As a result, we have adapted the JAWS scoring procedure, allowing the binding free energies of strongly bound water molecules to be * To whom correspondence should be addressed † University of Southampton ‡ Syngenta ¶ University of Edinburgh 1 calculated to a high degree of accuracy, requiring significantly less computational effort than more rigorous approaches. The combination of JAWS and GCMC offers a route to a rapid scheme capable of both locating and scoring water molecules for rational drug design.

“…[22] The procedure facilitates propagation of infrequent conformational changes across different simulations. It is also possible to use MC algorithms to sample rapidly configurations of the proteinligand complex using computationally inexpensive potential energy functions, and periodically to correct for systematic errors using a more accurate potential energy function.…”

Section: Precisionmentioning

confidence: 99%

Rigorous Free Energy Calculations in Structure‐Based Drug Design

Foloppe

Essex

2010

Molecular Informatics

Self Cite

Structure-based drug design could benefit greatly from computational methodologies that accurately predict the binding affinity of small compounds to target biomolecules. However, the current scoring functions used to rank compounds in virtual screens by docking are not sufficiently accurate to guide reliably the design of tight binding ligands. Thus, there is strong interest in methodologies based on molecular simulations of protein-ligand complexes which are perceived to be more accurate and, with advances in computing power, amenable to routine use. This report provides an overview of the technical details necessary to understand, execute and analyze binding free energy calculations, using free energy perturbation or thermodynamic integration methods. Examples of possible applications in structure-based drug design are discussed. Current methodological limitations are highlighted as well as a number of ongoing developments to improve the scope, reliability, and practicalities of free energy calculations. These efforts are paving the way for a more common use of free energy calculations in molecular design.