PDBsum entry 5ivt

Hydrolase/inhibitor

PDB id: 5ivt

Contents

Protein chains

99 a.a.

Ligands

ACT-6EE

6EE-ACT

Metals

_CL ×2

Waters ×196

PDB id:

5ivt

Name:

Hydrolase/inhibitor

Title:

Crystal structure of HIV protease complexed with [(1s)-1-[(s)-(4- chlorophenyl)-(3,5-difluorophenyl)methyl]-2-[[5-fluoro-4-[2-[(2r,5s)- 5-(2,2,2-trifluoroethylcarbamoyloxymethyl)morpholin-4-ium-2- yl]ethyl]pyridin-1-ium-3-yl]amino]-2-oxo-ethyl]ammonium

Structure:

Protease. Chain: a, b. Engineered: yes. Mutation: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: pol. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.15Å R-factor: 0.184 R-free: 0.193

Authors:

H.P.Su

Key ref:

C.J.Bungard et al. (2016). Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group. Acs Med Chem Lett, 7, 702-707. PubMed id: 27437081 DOI: 10.1021/acsmedchemlett.6b00135

Date:

21-Mar-16 Release date: 18-May-16

Protein chains

G0X8E8  (G0X8E8_9HIV1) -  Pol protein (Fragment) from Human immunodeficiency virus 1

Seq: 132 a.a.

Struc: 99 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acsmedchemlett.6b00135

Acs Med Chem Lett 7:702-707 (2016)

PubMed id: 27437081

Discovery of MK-8718, an HIV Protease Inhibitor Containing a Novel Morpholine Aspartate Binding Group.

C.J.Bungard, P.D.Williams, J.E.Ballard, D.J.Bennett, C.Beaulieu, C.Bahnck-Teets, S.S.Carroll, R.K.Chang, D.C.Dubost, J.F.Fay, T.L.Diamond, T.J.Greshock, L.Hao, M.K.Holloway, P.J.Felock, J.J.Gesell, H.P.Su, J.J.Manikowski, D.J.McKay, M.Miller, X.Min, C.Molinaro, O.M.Moradei, P.G.Nantermet, C.Nadeau, R.I.Sanchez, T.Satyanarayana, W.D.Shipe, S.K.Singh, V.L.Truong, S.Vijayasaradhi, C.M.Wiscount, J.P.Vacca, S.N.Crane, J.A.McCauley.

ABSTRACT

A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.