Calculated and Experimental Low-Energy Conformations of Cyclic Urea HIV Protease Inhibitors
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- 作者：C. Nicholas Hodge ; Patrick Y. S. Lam ; Charles J. Eyermann ; Prabhakar K. Jadhav ; Y. Ru ; Christina H. Fernandez ; George V. De Lucca ; Chong-Hwan Chang ; Robert F. Kaltenbach ; III ; Edward R. Holler ; Franci
- 刊名：Journal of the American Chemical Society
- 出版年：1998
- 出版时间：May 20, 1998
- 年：1998
- 卷：120
- 期：19
- 页码：4570 - 4581
- 全文大小：135K
- 年卷期：v.120,no.19(May 20, 1998)
- ISSN：1520-5126
文摘
One important factor influencing the affinity of a flexible ligandfor a receptor is the internal strainenergy required to attain the bound conformation. Calculation offully equilibrated ensembles of bound andfree ligand and receptor conformations are computationally not possiblefor most systems of biological interest;therefore, the qualitative evaluation of a novel structure as apotential high-affinity ligand for a given receptorcan benefit from taking into account both the bound and unbound(usually aqueous) low-energy geometries ofthe ligand and the difference in their internal energies. Althoughmany techniques for computationally generatingand evaluating the conformational preferences of small molecules areavailable, there are a limited number ofstudies of complex organics that compare calculated and experimentallyobserved conformations. To assessour ability to predict a priori favored conformations of cyclic HIVprotease (HIV-1 PR) inhibitors, conformationalminima for nine4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-ones I(cyclic ureas) were calculated using a hightemperature quenched dynamics (QD) protocol. Single crystal X-rayand aqueous NMR structures of freecyclic ureas were obtained, and the calculated low-energy conformationscompared with the experimentallyobserved structures. In each case the ring conformation observedexperimentally is also found in the lowestenergy structure of the QD analysis, although significantly differentring conformations are observed at onlyslightly higher energy. The 4- and 7-benzyl groups retain similarorientations in calculated and experimentalstructures, but torsion angles of substituents on the urea nitrogensdiffer in several cases. The data onexperimental and calculated cyclic urea conformations and their bindingaffinities to HIV-1 PR are proposedas a useful dataset for assessing affinity predictionmethods.