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Conformational analysis of HIV‐1 protease inhibitors: 2. Thioproline P 1 ′ Residue in the potent inhibitor KNI‐272
Author(s) -
Murcko Mark A.,
Govinda Rao B.,
Gomperts Roberto
Publication year - 1997
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/(sici)1096-987x(19970715)18:9<1151::aid-jcc4>3.0.co;2-q
Subject(s) - human immunodeficiency virus (hiv) , chemistry , residue (chemistry) , protease , protease inhibitor (pharmacology) , pharmacology , biochemistry , enzyme , virology , biology , antiretroviral therapy , viral load
The very potent HIV‐1 protease (HIV‐PR) inhibitor, KNI‐272,contains a norstatine–thioproline linkage atP 1 –P 1 ′. The three‐dimensional crystalstructure of this compound bound to HIV‐PR has recently been determined[Baldwin et al., Structure , 3 , 581 (1995)]. Thecrystal structure reveals a number of interesting interactions previouslyunseen in bound HIV‐PR inhibitors. Here, we employ high‐level abinitio calculations and molecular modeling to ascertain the strainenergy of the bound conformation of the norstatine–thioprolineportion of KNI‐272. Baldwin et al. suggested that two of the reasons forthe high potency of KNI‐272 are the rigidity of its backbone and a strongpreference for the norstatine–thioproline amide linkage to adopt atrans conformation. Our analysis shows that, on the contrary, there isstill considerable flexibility in the backbone of the norstatine‐basedinhibitor. Furthermore, in the gas phase and in solution, there are bothcis and trans conformations of the norstatine–thioproline amidelinkage which are low in energy. However, when bound in the active site ofHIV‐PR, KNI‐272 clearly has a strong preference for a trans conformation,which enables the formation of hydrogen bonds to the flap water. Ourcalculations, at level up to MP2/6‐31++G//HF/6‐31G*, suggest thatthe bound, trans amide conformation of the norstatine–thioproline“core” is still strained by 2–3 kcal/mol, primarily dueto the placement of the P 1 ′ thioproline carboxamide. Thisresult is consistent with those previously obtained for the relatedprotease inhibitor Ro 31‐8959 (Saquinovir), which also requires acarboxamide to adopt a high‐energy rotamer to preserve a good hydrogen bondto the flap water. However, the strain of the bound conformation of KNI‐272is clearly lower than that of Saquinovir. In addition, because thenorstatine linkage does not contain a basic amine (as do Saquinovir andJG‐365, for example) it should be easier to desolvate, which also assistsin binding. The relationship between KNI‐272, JG‐365, Saquinovir, andP 1 ′ proline‐containing substrate also is discussed. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1151–1166