scholarly journals Drug Resistance Conferred by Mutations Outside the Active Site through Alterations in the Dynamic and Structural Ensemble of HIV-1 Protease

2014 ◽  
Vol 136 (34) ◽  
pp. 11956-11963 ◽  
Author(s):  
Debra A. Ragland ◽  
Ellen A. Nalivaika ◽  
Madhavi N. L. Nalam ◽  
Kristina L. Prachanronarong ◽  
Hong Cao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Active Site ◽  
Structural Ensemble ◽  
Hiv 1

A Major Role for a Set of Non-Active Site Mutations in the Development of HIV-1 Protease Drug Resistance†

Biochemistry ◽  
2003 ◽  
Vol 42 (3) ◽  
pp. 631-638 ◽  
Author(s):  
Salman Muzammil ◽  
Patrick Ross ◽  
Ernesto Freire
Keyword(s):  
Drug Resistance ◽  
Active Site ◽  
Hiv 1 ◽  
Active Site Mutations

scholarly journals Evaluating the Substrate-Envelope Hypothesis: Structural Analysis of Novel HIV-1 Protease Inhibitors Designed To Be Robust against Drug Resistance

2010 ◽  
Vol 84 (10) ◽  
pp. 5368-5378 ◽  
Author(s):  
Madhavi N. L. Nalam ◽  
Akbar Ali ◽  
Michael D. Altman ◽  
G. S. Kiran Kumar Reddy ◽  
Sripriya Chellappan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitors ◽  
Active Site ◽  
Crystallographic Analysis ◽  
Van Der Waals Interactions ◽  
Drug Resistant ◽  
Design Strategies ◽  
Resistance Mutations ◽  
Hiv 1 ◽  
Substrate Envelope

ABSTRACT Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized using three different approaches with and without substrate-envelope constraints. A subset of 16 representative inhibitors with binding affinities to wild-type protease ranging from 58 nM to 0.8 pM was chosen for crystallographic analysis. The inhibitor-protease complexes revealed that tightly binding inhibitors (at the picomolar level of affinity) appear to “lock” into the protease active site by forming hydrogen bonds to particular active-site residues. Both this hydrogen bonding pattern and subtle variations in protein-ligand van der Waals interactions distinguish nanomolar from picomolar inhibitors. In general, inhibitors that fit within the substrate envelope, regardless of whether they are picomolar or nanomolar, have flatter profiles with respect to drug-resistant protease variants than inhibitors that protrude beyond the substrate envelope; this provides a strong rationale for incorporating substrate-envelope constraints into structure-based design strategies to develop new HIV-1 protease inhibitors.

scholarly journals Molecular docking-based screening for novel inhibitors of the human immunodeficiency virus type 1 protease that effectively reduce the viral replication in human cells

2020 ◽  
Author(s):  
Carla Mavian ◽  
Roxana M Coman ◽  
Xinrui Zhang ◽  
Steve Pomeroy ◽  
David A. Ostrov ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Active Site ◽  
Ex Vivo ◽  
Human Cells ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Therapeutic Pressure ◽  
Hiv 1

AbstractTherapeutic pressure by protease inhibitors (PIs) contributes to accumulation of mutations in the HIV type 1 (HIV-1) protease (PR) leading to development of drug resistance with subsequent therapy failure. Current PIs target the active site of PR in a competitive manner. Identification of molecules that exploit non-active site mechanisms of inhibition is essential to overcome resistance to current PIs. Potential non-active site HIV-1 protease (PR) inhibitors (PI) were identified by in silico screening of almost 140,000 molecules targeting the hinge region of PR. Inhibitory activity of best docking compounds was tested in an in vitro PR inhibition biochemical assay. Five compounds inhibited PR from multiple HIV-1 subtypes in vitro and reduced replicative capacity by PI-sensitive or multi-PI resistant HIV-1 variants in human cells ex vivo. Antiviral activity was boosted when combined with Ritonavir, potentially diminishing development of drug resistance, while providing effective treatment for drug resistant HIV-1 variants.

scholarly journals Touching the heart of HIV-1 drug resistance: the fingers close down on the dNTP at the polymerase active site

1999 ◽  
Vol 6 (5) ◽  
pp. R137-R146 ◽  
Author(s):  
Stefan G. Sarafianos ◽  
Kalyan Dasi ◽  
Jianping Dingi ◽  
Paul L. Boyer ◽  
Stephen H. Hughes ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Active Site ◽  
Hiv 1

Drug resistance among patients with HIV-1

2013 ◽  
Vol 4 (5) ◽  
pp. 317-323
Author(s):  
Miłosz Parczewski
Keyword(s):  
Drug Resistance ◽  
Hiv 1
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