Binding modes of CCR5-targetting HIV entry inhibitors: Partial and full antagonists

Abstract

Since the CC-chemokine receptor 5 (CCR5) was identified as a major coreceptor for human immunodeficiency virus type 1 (HIV-1) entry into a host cell, CCR5-targetting HIV entry inhibitors have been developed and some of them are currently in clinical trials. Most of these inhibitors also inhibit the physiological chemokine reaction function of CCR5, which is so far considered to be safe to patients based on the observation that individuals that naturally lack CCR5 do not show apparent health problems. Nevertheless, to minimize the toxicity and side effects, it would be ideal to preserve the chemokine receptor activity. In this work, we simulated the flexible docking of two small molecule inhibitors to CCR5 in a solvated phospholipid bilayer environment. One of the inhibitors, aplaviroc has a unique feature of preserving two of the natural chemokine ligands binding to CCR5 and subsequent activation whereas the other one, SCH-C fully blocks chemokine-CCR5 interactions. Our results revealed significantly different binding modes of these two inhibitors although both established extensive interaction networks with CCR5. Comparison of the different binding modes suggests that avoiding the deep insertion of inhibitors into the transmembrane helix bundle may be able to preserve chemokine-CCR5 interactions. These results could help design HIV coreceptor activity-specific inhibitors.

Closing the door on flaviviruses: Entry as a target for antiviral drug design

“…These studies have invited an alternative focus from inhibition of RNA replication towards blocking structural transitions required for efficient virus spread. Similar strategies were previously employed for antiviral design against the rhinoviruses (Badger et al, 1988;Hadfield, Diana, and Rossmann, 1999;Heinz et al, 1989;Rossmann, 1994;Rossmann et al, 2000) and enteroviruses (Padalko et al, 2004;Rossmann et al, 2000), and have recently gained momentum in other fields such as HIV (Copland, 2006;Veiga, Santos, and Castanho, 2006;Wang and Duan, 2007) and influenza (Hsieh and Hsu, 2007).…”

HIV-1 Infection: The Functional Importance of SDF1, CCR2 and CCR5 in Protection and Therapeutics

“…Aplaviroc a lead compound derived from spirodiketopiperazine interacts to CCR5 at Glu 283 by salt bridge, Thr 195 by hydroxyl group and at Ile198-Thr115-Phe109 hydrophobic pocket by cyclohexyl group blocking HIV1 R5 strains infection, but unfortunately this compound showed liver toxicity in primary trials and discontinued from further modifications [23]. Although the structure of these antagonist is different from each other but still all of them share the same binding pocket onto CCR5 receptor with differential binding mode [28]. INCB 3284 dimesylate, BMS CCR2 22, JNJ 27141491, RS 504393, Teijin compound 1, RS 102895 hydrochloride, are selective CCR2 antagonist (Figure 1), where INCB 3284 dimesylate and JNJ 27141491 are orally bio available for their potency [29][30][31][32][33].…”

Allosteric Modulation of Chemokine Receptors

“…There is considerable evidence that chemokine receptors form functional dimers [61][62][63][64][65][66]. Dimerization can be thought of in allosteric terms as having two functional consequences.…”