Are Automated Molecular Dynamics Simulations and Binding Free Energy Calculations Realistic Tools in Lead Optimization? An Evaluation of the Linear Interaction Energy (LIE) Method

Abstract

An extensive evaluation of the linear interaction energy (LIE) method for the prediction of binding affinity of docked compounds has been performed, with an emphasis on its applicability in lead optimization. An automated setup is presented, which allows for the use of the method in an industrial setting. Calculations are performed for four realistic examples, retinoic acid receptor gamma, matrix metalloprotease 3, estrogen receptor alpha, and dihydrofolate reductase, focusing on different aspects of the procedure. The obtained LIE models are evaluated in terms of the root-mean-square (RMS) errors from experimental binding free energies and the ability to rank compounds appropriately. The results are compared to the best empirical scoring function, selected from a set of 10 scoring functions. In all cases, good LIE models can be obtained in terms of free-energy RMS errors, although reasonable ranking of the ligands of dihydrofolate reductase proves difficult for both the LIE method and scoring functions. For the other proteins, the LIE model results in better predictions than the best performing scoring function. These results indicate that the LIE approach, as a tool to evaluate docking results, can be a valuable asset in computational lead optimization programs.

Efficient free energy calculations on small molecule host‐guest systems—A combined linear interaction energy/one‐step perturbation approach

“…It should be very feasible to perform LIE/OS calculations in a realistic lead-optimization programme. 10 Third, in such a programme, it is commonly considered to be very useful to spend the computational effort on simulations of the real compounds (P:L q ), such that molecular insight in the behavior of these compounds may also be obtained. Molecular explanations for the calculated affinities may be obtained and suggestions for novel compounds are subsequently readily made.…”

“…Scoring functions are not accurate enough for this task. 9,10 In recent years, a number of methods have been developed that are efficient enough to be applied to these numbers of molecules and that are accurate enough to calculate meaningful affinities. 11,12 One example is the linear interaction energy (LIE) method, which is based on linear response theory and estimates the binding free energy of a compound from the ensemble average of the potential interaction energy.…”

The impact of accelerator processors for high-throughput molecular modeling and simulation

“…Thermodynamics integration (TI) [31], steered molecular dynamics [36], umbrella sampling [5] and linear interaction energy (LIE) approaches [42] can be applied to several hundred protein structures at once. Furthermore, standard molecular dynamics could be of great help to the understanding of a plethora of molecular and cellular processes.…”

Análise e caracterização molecular, estrutural e populacional de proteases de HIV-1 do Estado de São Paulo.

“…Através do método semi-empírico de energia linear de interação (LIE, linear interaction energy, Equação 3), a energia livre de ligação (ΔG lig ) é dada pela mudança de estado entre a interação do ligante (l) em solução (w) e o ligante dentro de seu receptor proteico (p) (Aqvist et al, 2002). Para condições onde o ligante e o receptor são bem estudados, há grande ganho computacional e boa aproximação de energias medidas (Stjernschantz et al, 2006). .…”

“…e S1' e de nelfinavir sugeriram um comportamento mais similar ao de proteases selvagens; e em outros casos, como as mutações M46L e V82A, as mesmas mutações (Aqvist et al, 2002), e proteína e ligante são bastante conhecidos (Stjernschantz et al, 2006).…”