Inhibitors of Aspartyl Proteinases

Abdel-Meguid, Sherin S.

doi:10.1002/med.2610130605

Cited by 52 publications

(12 citation statements)

References 191 publications

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“…The inhibitor binds in the activesite cavity in an extended conformation. It is held by a set of hydrophobic and hydrogen-bonding interactions, many of which are conserved in similar structures (Abdel-Meguid, 1993;Wlodawer & Erickson, 1993). Every heteroatom of the inhibitor is hydrogen-bonded to an atom of the protein, either directly or indirectly through a water molecule ( Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Three-dimensional structure of a simian immunodeficiency virus protease/inhibitor complex. Implications for the design of human immunodeficiency virus type 1 and 2 protease inhibitors

Zhao

Winborne²,

Minnich³

et al. 1993

Biochemistry

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Simian immunodeficiency virus (SIV) proteins have considerable amino acid sequence homology to those from human immunodeficiency virus (HIV); thus monkeys are considered useful models for the preclinical evaluation of acquired immune deficiency syndrome (AIDS) therapeutics. We have crystallized and determined the three-dimensional structure of SIV protease bound to the hydroxyethylene isostere inhibitor SKF107457. Crystals of the complex were grown from 25-32% saturated sodium chloride, by the hanging drop method of vapor diffusion. They belong to the orthorhombic space group I222, with a = 46.3 A, b = 101.5 A, and c = 118.8 A. The structure has been determined at 2.5-A resolution by molecular replacement and refined to a crystallographic discrepancy factor, R (= sigma parallel Fo magnitude of - magnitude of Fc parallel/sigma magnitude of Fo magnitude of), of 0.189. The overall structure of the complex is very similar to previously reported structures of HIV-1 protease bound to inhibitors. The inhibitor is bound in a conformation that is almost identical to that found for the same inhibitor bound to HIV-1 protease, except for an overall translation of the inhibitor, varying along the backbone atoms from about 1.0 A at the termini to about 0.5 A around the scissile bond surrogate. The structures of the SIV and HIV-1 proteins vary significantly only in three surface loops composed of amino acids 15-20, 34-45, and 65-70. Superposition of the 1188 protein backbone atoms from the two structures gives an rms deviation of 1.0 A; this number is reduced to 0.6 A when atoms from the three surface loops are eliminated from the rms calculation.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Resultsmentioning

confidence: 99%

Three-dimensional structure of a simian immunodeficiency virus protease/inhibitor complex. Implications for the design of human immunodeficiency virus type 1 and 2 protease inhibitors

Zhao

Winborne²,

Minnich³

et al. 1993

Biochemistry

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“…The inhibitor should be able to lower renin blood pressure in hypertensive patients; be orally bioavailable to compete in the market place with ACE inhibitors; advantageous relative to other antihypertensive agents; potent; specific for renin versus pepsin; nontoxic; and metabolically stable. Progress toward achieving most of these requirements has been substantial and systematic structural modifications lead to molecules with significantly improved properties such as the development of orally bioavailable inhibitors ready for preclinical and clinical trials [152].…”

Section: Renin Inhibitorsmentioning

confidence: 99%

Medicinal Chemistry of α‐Hydroxy‐β‐Amino Acids

Ziora

Skwarczynski

Kiso

2011

Amino Acids, Peptides and Proteins in Organic Chemistry

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“…A subunidade hidroxietileno do amino ácido não usual statina, presente no derivado (27), pode ser considerado um isóstero adequado para a ligação amídica e foi utilizado como base para o desenvolvimento de inibidores que mimetizavam o estado de transição tetraédrico da hidrólise 30 . Diversos inibidores de HIV protease foram desenvolvidos posteriormente utilizando grupamentos como hidroxietileno, diidroxietileno ou difluorocetonas, entre outros, como isósteros de amida 30,68,71,72 . O isóstero não hidrolizável de amida mais simples, a amida reduzida (alquil amina), não demonstrou ser um grupamento adequado para inibidores de HIV PR 34 .…”

Section: Inibidores De Hiv Proteaseunclassified