A comparison of the AMBER*, OPLSAA and HF potential energy surfaces for a series of diastereomeric cyclic urea HIV-1 inhibitors

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Abstract

The LM:MC conformational search method was used to identify the low energy structures on the OPLS-AA/GBSA(water) and AMBER*/GBSA(water) surfaces for a diastereomeric series of cyclic urea molecules that have been shown to be potent inhibitors of the HIV-1 protease enzyme. The lowest energy structures from each search were then subjected to geometry optimization and frequency analysis using the HF/6-311G** method in conjunction with the self-consistent reaction field (SCRF) treatment for water. A comparison of the diastereomeric energies and structures indicates that the OPLSAA/GBSA(water) surface is in good agreement with the HF/6-311G**/SCRF(water) surface.

Introduction

Force-field based molecular modeling is becoming an increasingly important tool as hardware costs decrease, processing speeds increase and software products become more numerous and easier to use. However, in order for such tools to be predictive, the potential energy surface generated by the force-field must accurately describe the molecular system under study and such a surface must be adequately sampled in a reasonable amount of time [1]. This study examines the ability of the OPLSAA [2], [3] and AMBER* [4] force-fields, in conjunction with the GBSA continuum solvent model [5], [6], [7], [8], [9], [10], to describe accurately the potential energy surface of a diastereomeric series of cyclic urea HIV-1 protease inhibitors. The accuracy of the force-fields will be measured by comparison with the HF/6-311G** surface using the self-consistent reaction field theory (SCRF) to describe the effects of the solvent environment. The HF/6-311G** level of theory has been shown to provide reliable conformational energies [11], [12] while the SCRF model for water is able to provide solvation free energies in quantitative agreement with experimental measurements [13].

The cyclic urea molecule (Fig. 1) contains a relatively rigid seven-membered urea ring scaffold that helps to orient the benzyl ‘arms’ for optimal interaction with the S1/S1' and S2/S2' hydrophobic pockets of the HIV protease enzyme. There are four contiguous chiral centers that give rise to 10 stereoisomers. Nine of these stereoisomers have been synthesized and the RSSR diastereomer displays the highest binding affinity for the HIV-1 protease [14]. Of the 10 stereoisomers, there are four enantiomeric pairs (RRRR/SSSS, RSSR/SRRS, RSSS/RRRS and RSRR/SSRS) and therefore six unique diastereomers in an achiral environment (RRRR, RSSR, RSSS, RSRR, RSRS and RRSS). Crystal structures for a variety of RSSR cyclic urea inhibitors that are similar to 1 have been determined in the presence of the active site [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25] and as the free ligand [16], [23], [26]. In addition, an NMR solution structure is available [27]. In all of these studies, the RSSR inhibitor adopts a chair conformation in the presence and absence of the active site and in the liquid and solid phase indicating that the system is preorganized for binding to the HIV protease. In this study, we will investigate the potential energies surfaces of these six unique diastereomers in order to validate a force-field for use in future conformational and molecular dynamics studies.

Section snippets

Methods

The conformational searches and energetic analyses using AMBER*/GBSA(water) and OPLSAA/GBSA(water) were performed with version V7.2 of the MacroModel [28] suite of software programs running on 800 MHz Athlon PCs under the RedHat LINUX 6.2 operating system. Quantum calculations were performed with Jaguar V4.0 [29].

Results and discussion

The RSSR diastereomer was experimentally determined to be the tightest HIV-1 protease binder [14]; therefore, we began with this molecule in our process of force-field verification. For efficiency reasons, it was of interest to utilize the united-atom AMBER* treatment where hydrogens on carbon atoms are not explicitly considered, but described with the ‘super-atom’ approach [35]. A conformational search was performed on the all-atom and united-atom AMBER*/GBSA(water) surfaces. Surprisingly, the

Acknowledgements

H.C. and M.R. would like to acknowledge summer undergraduate research fellowships provided by the Pfizer SURF program (H.C.) and the Merck Undergraduate Summer Research Program administered by the American Association for the Advancement of Science (M.R.). Acknowledgment is made to the Donors of the Petroleum Research Fund, administered by the American Chemical Society, and the National Science Foundation, under grant CHE-0211577, for support of this research. Computational resources were

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