Vicriviroc

CCR5 Receptor Structure and Allosteric Modulation

CCR5 is a 7-transmembrane segment receptor belonging to the GPCR family. wikipedia.orgnih.govdaignet.de Small molecule CCR5 inhibitors, including vicriviroc, bind to a hydrophobic cavity located within the transmembrane domain of CCR5. nih.govnih.gov This binding site is distinct from the binding sites for natural chemokine ligands and the HIV-1 gp120 protein, indicating an allosteric mechanism of action. nih.govfrontiersin.org Allosteric modulation involves binding to a site distinct from the orthosteric site (where the natural ligand binds) and inducing a conformational change in the receptor that affects orthosteric ligand binding or receptor function. nih.govresearchgate.netnih.gov

Interaction with HIV-1 gp120 and gp41

HIV-1 entry into host cells is initiated by the binding of the viral envelope glycoprotein (Env) to the host cell's CD4 receptor. wikipedia.orgnih.govdaignet.deplos.org The Env is a trimer composed of two subunits: gp120 and gp41. daignet.deplos.orgnih.gov The gp120 subunit is responsible for binding to CD4 and the chemokine co-receptor, typically CCR5 for R5-tropic strains. wikipedia.orgnih.govdaignet.deplos.org This initial binding to CD4 induces conformational changes in gp120, exposing a high-affinity binding site for the co-receptor. daignet.deplos.org The interaction between gp120 and CCR5 then triggers further conformational changes in the gp41 subunit, which mediates the fusion of the viral membrane with the host cell membrane, allowing the viral genetic material to enter the cell. wikipedia.orgdaignet.deplos.orgnih.gov The gp41 protein undergoes a refolding process, forming a six-helix bundle that drives membrane fusion. daignet.denih.govasm.org

Noncompetitive Allosteric Antagonism

This compound is characterized as a noncompetitive allosteric antagonist of CCR5. nih.govwikipedia.orgnih.govnih.gov This means that this compound does not compete directly with the natural chemokine ligands or the viral gp120 for the same binding site on CCR5. nih.gov Instead, it binds to a distinct allosteric site within the transmembrane domain. nih.govnih.gov Binding to this site induces a conformational change in the CCR5 receptor that prevents or significantly reduces the ability of gp120 to bind effectively to its recognition site on the receptor, thereby blocking viral entry. nih.govwikipedia.org

Specific Residue Interactions within the CCR5 Hydrophobic Pocket

This compound binds to a small hydrophobic pocket located between the transmembrane helices near the extracellular surface of the CCR5 receptor. nih.govwikipedia.org Specific interactions between this compound and residues within this pocket have been described. The trifluoromethyl phenyl group of this compound is thought to interact strongly with the I198 residue on the fifth transmembrane helix (TM5) of CCR5 through hydrophobic interactions. wikipedia.org Additionally, electrostatic interactions may occur between the positively charged tertiary nitrogen group of this compound and the hydrophilic region provided by the E283 residue on TM7 of CCR5. wikipedia.orgplos.org Other residues predicted to be involved in strong interactions include Y108 on TM3 and Y251 on TM6. wikipedia.orgplos.org Studies suggest that while this compound and maraviroc bind to a similar hydrophobic pocket, they do so in subtly different ways, interacting with distinct amino acids, which may lead to the stabilization of different CCR5 conformations. nih.gov

Predicted Key Residue Interactions of this compound with CCR5

Note: Interactions are based on research findings and predictions. wikipedia.orgplos.org

Inhibition of Viral Entry

HIV-1 entry into target cells is a multi-step process initiated by the binding of the viral envelope glycoprotein gp120 to the CD4 receptor on the host cell surface. wikipedia.orghivclinic.ca This interaction induces a conformational change in gp120, exposing a binding site for a co-receptor, which is typically either CCR5 or CXCR4. wikipedia.orghivclinic.ca CCR5-tropic (R5) strains of HIV-1 utilize the CCR5 co-receptor for entry. nih.govresearchgate.netnih.gov

This compound functions as an entry inhibitor by specifically binding to the CCR5 receptor. bocsci.comnih.govresearchgate.netnih.gov It is described as a noncompetitive allosteric antagonist that binds to a hydrophobic pocket located between the transmembrane helices near the extracellular surface of the CCR5 receptor. wikipedia.orgdrugbank.comnih.gov This binding event induces a conformational change in the extracellular segment of CCR5, which in turn prevents the interaction between the viral gp120 protein and the CCR5 receptor. wikipedia.orgdrugbank.comnih.gov By blocking this crucial co-receptor binding step, this compound effectively prevents the fusion of the viral and cellular membranes, thereby inhibiting the entry of CCR5-tropic HIV-1 into target cells. wikipedia.orgontosight.aidrugbank.comnih.gov

Studies have shown that this compound potently inhibits the replication of a broad spectrum of CCR5-tropic HIV-1 isolates, including those that are genetically diverse and resistant to other classes of antiretroviral drugs. nih.govnih.gov Its antiviral activity has been demonstrated in various in vitro assays. For instance, this compound has shown potent activity against a panel of 30 R5-tropic HIV-1 isolates with EC50 values ranging from 0.04 nM to 2.3 nM. selleckchem.combiocrick.comcaymanchem.com It is also effective against viruses with defined resistance patterns to reverse transcriptase inhibitors (RTIs), protease inhibitors (PIs), or fusion inhibitors. selleckchem.combiocrick.com

Impact on Chemokine-Induced Cellular Functions

Beyond its role in viral entry, CCR5 is a G protein-coupled receptor that mediates cellular responses to its endogenous ligands, such as the chemokines MIP-1α, MIP-1β, and RANTES. nih.govdrugbank.com These interactions trigger downstream signaling pathways involved in various cellular functions, including chemotaxis, calcium flux, and GTPγS binding. nih.govresearchgate.netnih.gov As a CCR5 antagonist, this compound interferes with the binding of these chemokines, thereby inhibiting these signaling events. nih.govresearchgate.netnih.govhodoodo.com

Research findings from functional assays confirm that this compound acts as a receptor antagonist by inhibiting the signaling of CCR5 induced by chemokines. nih.govresearchgate.netnih.govhodoodo.com

Chemotaxis: this compound has been shown to inhibit chemokine-mediated migration of cells expressing human CCR5. In a chemotaxis assay using a mouse Ba/F3 cell line stably expressing recombinant human CCR5, this compound demonstrated potent inhibition of the chemotactic response induced by MIP-1α, with an IC50 value below 1 nM. nih.govresearchgate.netbiocrick.comcaymanchem.com Similar inhibitory effects were observed when RANTES and MIP-1β were used as chemoattractants. nih.gov

Calcium Flux: Stimulation of CCR5 by its ligands leads to an increase in intracellular calcium levels. This compound inhibits this intracellular calcium release induced by receptor stimulation. nih.govresearchgate.netbiocrick.com In U-87-CCR5 cells, this compound inhibited intracellular calcium release induced by RANTES with an IC50 of 16 nM. selleckchem.com Importantly, this compound treatment alone did not induce calcium signaling, confirming its antagonist properties. nih.govresearchgate.netselleckchem.com

GTPγS Binding: Receptor activation of G proteins involves the exchange of GDP for GTP, which can be measured using the binding of the non-hydrolyzable GTP analog, GTPγS. CCR5 activation by chemokines stimulates GTPγS binding to the associated G proteins. This compound inhibits this chemokine-induced GTPγS binding, indicating its ability to block downstream signaling. nih.govresearchgate.netnih.govhodoodo.com In a GTPγS binding assay, this compound potently inhibited RANTES-induced signaling with a mean IC50 of 4.2 ± 1.3 nM. nih.govselleckchem.combiocrick.com Neither this compound nor a comparator compound (SCH-C) alone induced a signal in this assay, further supporting their antagonist characteristics. nih.gov

These functional assays collectively demonstrate that this compound is a potent antagonist of the CCR5 receptor capable of inhibiting receptor function triggered by its natural chemokine ligands. nih.govresearchgate.net

Summary of In Vitro Functional Assay Results

Antiviral Activity Against R5-tropic HIV-1 Isolates

Activity against R5-tropic HIV-1 Isolates

This compound has shown potent inhibitory activity against R5-tropic HIV-1 isolates, which utilize the CCR5 coreceptor for entry into host cells. nih.govnih.govasm.org This is particularly relevant as R5-tropic viruses are responsible for the majority of HIV-1 transmissions and are typically the predominant species during the early stages of infection. tandfonline.comoup.com Studies using a panel of diverse R5-tropic HIV-1 isolates have shown this compound to be a potent inhibitor of viral replication. nih.govselleckchem.com

In a study evaluating the antiviral activity of this compound against 30 R5-tropic HIV-1 isolates from various genetic clades, this compound potently inhibited all tested isolates. nih.govselleckchem.com The geometric mean EC50 values ranged between 0.04 nM and 2.3 nM, while the EC90 values ranged from 0.45 nM to 18 nM. nih.govselleckchem.com this compound was consistently more active than SCH-C, an earlier CCR5 antagonist, against these isolates, showing 2- to 40-fold lower mean EC50 values. selleckchem.comresearchgate.net

Data compiled from research findings. nih.govselleckchem.com

Activity against Drug-Resistant HIV-1 Strains

A significant challenge in HIV treatment is the emergence of drug-resistant viral strains. nih.gov Preclinical studies evaluated the activity of this compound against HIV-1 isolates resistant to existing antiretroviral drugs from other classes, such as reverse transcriptase inhibitors (RTIs) and protease inhibitors (PRIs). nih.govnatap.org

This compound demonstrated activity against viruses with RTI, PRI, or multidrug resistance (MDR) phenotypes. nih.govselleckchem.com The EC50 values against these resistant viruses were comparable to those observed for wild-type control viruses. nih.gov This finding is expected because this compound targets an early step in the viral life cycle (viral entry) that occurs prior to the targets of RTIs and PRIs (reverse transcription and virion maturation, respectively). nih.govselleckchem.com this compound also exhibited potent antiviral activity against recombinant viruses carrying multiple drug resistance mutations, including those resistant to the fusion inhibitor enfuvirtide. natap.org This suggests that resistance to other drug classes does not necessarily confer cross-resistance to this compound. natap.orgoup.com

However, resistance to CCR5 antagonists can emerge, often involving mutations in the viral envelope protein gp120, particularly in the V3 loop, or changes in coreceptor usage. tandfonline.comoup.com Studies have shown that this compound-resistant strains can exhibit cross-resistance to other CCR5 inhibitors that share similar interaction sites on the CCR5 coreceptor. oup.com

Mechanisms of Synergy with Different Antiretroviral Classes

In vitro drug combination studies have confirmed that this compound can act synergistically with drugs from various approved antiretroviral classes. nih.govnih.govnatap.orgasm.org Synergy has been observed with nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine and lamivudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz, and the protease inhibitor indinavir. asm.org Additionally, this compound has shown synergy with the fusion inhibitor enfuvirtide, indicating that simultaneously targeting multiple steps in the viral entry process can lead to cooperative effects. asm.org

The mechanisms underlying the synergy between this compound and other antiretrovirals are related to their distinct targets in the HIV-1 life cycle. By blocking viral entry at the CCR5 coreceptor, this compound reduces the number of target cells infected, while drugs from other classes inhibit subsequent steps like reverse transcription, protein processing, or viral fusion. natap.orgmsdmanuals.com This multi-targeted approach can lead to enhanced viral inhibition compared to the use of single agents. tandfonline.com

Synergy has also been reported between this compound and other CCR5 inhibitors, such as the monoclonal antibody PRO 140 and maraviroc, suggesting that targeting different sites or inducing distinct conformational changes on the CCR5 receptor can result in synergistic antiviral effects. asm.orgresearchgate.net Competition binding studies support the idea that these agents may interact with CCR5 in different ways. asm.org

Furthermore, studies have shown that reducing CCR5 density on target cells with agents like rapamycin can enhance the antiviral activity of this compound, including against this compound-resistant strains, suggesting a potential synergistic interaction through modulation of the host cell environment. pnas.orgnih.gov

Competitive Binding Assays

Competition binding assays are used to determine the affinity of a compound for its target receptor. nih.govnih.gov These assays have shown that this compound binds specifically to the CCR5 receptor. nih.govnih.gov

In competition binding assays, this compound demonstrated a higher binding affinity for CCR5 compared to SCH-C. nih.govnih.govselleckchem.comresearchgate.net The reported Ki value for this compound binding to CCR5 is 0.8 nM, while that for SCH-C is 2.6 nM. selleckchem.com This higher affinity is thought to contribute to this compound's greater antiviral potency observed in cell-based assays. selleckchem.comresearchgate.net

Binding kinetics studies have also shown that this compound dissociates from CCR5 at a slower rate than maraviroc, another CCR5 antagonist, which may offer a pharmacodynamic advantage in maintaining sustained receptor occupancy. natap.org

Functional assays, including the inhibition of calcium flux, guanosine 5′-[35S]triphosphate (GTPγS) exchange, and chemotaxis, have further confirmed that this compound acts as a receptor antagonist by inhibiting the signaling of CCR5 by chemokines like RANTES. nih.govnih.govselleckchem.comresearchgate.net this compound inhibits RANTES-induced intracellular calcium release and GTPγS binding to CCR5 membranes, demonstrating its ability to block downstream signaling events mediated by the receptor. selleckchem.comresearchgate.net

Inhibition of CCR5-Mediated Signaling Pathways

This compound acts as a potent antagonist of the CCR5 receptor, effectively inhibiting its function. nih.gov Studies utilizing functional assays such as calcium flux, chemotaxis, and GTPγS exchange have demonstrated its ability to block signaling mediated by chemokines that bind to CCR5. nih.gov

In chemotaxis assays using a mouse Ba/F3 cell line stably expressing human CCR5, this compound demonstrated potent inhibition of the chemotactic response induced by MIP-1α, with IC50 values below 1 nM. nih.gov Similar inhibitory effects were observed when RANTES and MIP-1β were used to induce chemotaxis. nih.gov

In U-87-CCR5 cells, this compound inhibited intracellular calcium release triggered by the ligand RANTES, with an IC50 of 16 nM. selleckchem.com Importantly, this compound treatment alone did not stimulate calcium release in this assay, confirming its antagonist properties. nih.govselleckchem.com

The ability of this compound to inhibit CCR5 receptor signaling was further demonstrated in a GTPγS exchange assay using membranes from HTS-hCCR5 cells. nih.gov this compound potently inhibited RANTES-induced GTPγS binding, with a mean IC50 of 4.2 ± 1.3 nM. nih.govselleckchem.com Neither this compound nor a related compound, SCH-C, induced a signal in this assay, further supporting their antagonist nature. nih.gov

This compound has also been shown to block CCL5-activated signaling mediated by CCR5 in basal-like human breast cancer cells, with IC50 values reported below 30 nM. aacrjournals.org

The following table summarizes some of the in vitro efficacy data regarding the inhibition of CCR5-mediated signaling pathways:

Preclinical Pharmacokinetic Considerations (in vitro metabolism)

Metabolic Pathways and Enzyme Involvement (e.g., CYP3A4, CYP3A5, CYP2C9)

In vitro metabolism studies using human liver microsomes have been conducted to identify the cytochrome P450 (CYP) enzymes responsible for the biotransformation of this compound. nih.govresearchgate.net These studies indicate that this compound is metabolized via several oxidative pathways, including N-oxidation, O-demethylation, N,N-dealkylation, N-dealkylation, and oxidation to a carboxylic acid metabolite. nih.govresearchgate.net

The primary enzyme responsible for the formation of the major this compound metabolites in human liver microsomes is CYP3A4. nih.gov Recombinant human CYP3A4 has been shown to catalyze the formation of all identified metabolites. nih.govresearchgate.net

CYP3A5 and CYP2C9 also play roles in this compound biotransformation, although they are considered minor contributors compared to CYP3A4. nih.govresearchgate.net Recombinant human CYP3A5 catalyzes the formation of N-oxidation (M2/M3) and N-dealkylation (M41) metabolites, while CYP2C9 primarily catalyzes the formation of the O-demethylation metabolite (M15). nih.gov

Studies using CYP3A4 inhibitors like ketoconazole and azamulin have demonstrated potent inhibition of the formation of multiple this compound metabolites in human liver microsomes. nih.gov A CYP3A4/5-specific monoclonal antibody also significantly inhibited the formation of all metabolites, by 86% to 100%. nih.gov

Protein Binding Characteristics

Plasma protein binding is an important consideration in pharmacokinetics as only unbound drug is generally considered free to exert therapeutic effects, be metabolized, or be excreted. bioivt.comsygnaturediscovery.com

Studies evaluating the binding of this compound to human plasma proteins have shown it to be moderately bound. nih.gov Approximately 16% of the compound remained unbound in human plasma when evaluated at a concentration of 0.94 µM using ultrafiltration. nih.govresearchgate.net

In vitro studies performed with increasing amounts of human serum showed no significant effect of serum concentration on the antiviral activity of this compound at concentrations up to 50% in the cultures. nih.gov Based on these findings, it was not anticipated that serum protein binding would have a significant impact on the in vivo antiviral efficacy of this compound. nih.gov

Mutations in HIV-1 gp120 V3 Loop Region

The V3 loop of HIV-1 gp120 is a critical determinant of coreceptor usage and a primary site for mutations conferring resistance to CCR5 antagonists like this compound. mdpi.com Studies have shown that amino acid substitutions within the V3 loop are frequently associated with reduced susceptibility to this compound. oup.comasm.orgnih.govnih.govasm.org These mutations can arise sequentially, leading to a complete loss of drug activity. nih.gov

Specific mutations in the V3 loop have been identified in this compound-resistant viruses, although a consistent, conserved pattern across all subjects is not always observed. oup.comnih.gov Examples of V3 loop mutations associated with this compound resistance include Q18E, D25G, and G17A, which were observed in one study and linked to progressive reductions in susceptibility. oup.com The K10R substitution has also been noted in some this compound-resistant viruses. oup.com In a study of an HIV-1 subtype D isolate, V3 loop mutations Q315E and R321G were found to be essential for resistance. nih.gov

However, the impact of V3 loop mutations on this compound susceptibility can depend on the context of the entire envelope glycoprotein sequence. nih.gov Viruses with identical V3 loop sequences have shown varying degrees of susceptibility, indicating that other regions of gp160 also play a role. oup.com

Mutations Outside the V3 Loop (e.g., C4)

While the V3 loop is a major contributor to this compound resistance, mutations in other regions of gp120 and even gp41 can also play a significant role. oup.comnih.govoup.com Substitutions outside the V3 loop, such as in the C4 domain of gp120 and the fusion peptide of gp41, have been shown to contribute to the resistance phenotype. oup.comnih.govoup.com

For instance, in the study involving the HIV-1 subtype D isolate, in addition to V3 loop mutations, changes in the C4 domain, specifically E328K and G429R, contributed significantly to the infectivity of the resistant variant. nih.gov These mutations outside the V3 loop can modulate the magnitude of resistance. researchgate.net Studies have indicated that mutations both within and outside the V3 loop contribute to the phenotypic resistance to this compound, and there is no clearly conserved pattern of mutations in gp160 associated with this resistance. nih.gov

Adaptation to Drug-Bound CCR5 Conformation

A key mechanism of resistance to CCR5 antagonists like this compound involves the virus adapting to utilize the drug-bound conformation of the CCR5 coreceptor for entry. oup.comasm.orgnih.govnih.govresearchgate.net this compound, similar to other CCR5 antagonists, binds to a hydrophobic pocket within the transmembrane domains of CCR5, inducing conformational changes in the receptor. oup.comasm.orgnih.govasm.org Resistant viruses develop alterations in their envelope protein that allow them to interact effectively with this altered, drug-bound state of CCR5. oup.comasm.org

This adaptation can manifest phenotypically as a reduction in the maximum percent inhibition (MPI) of viral entry by the drug, rather than a significant increase in the half-maximal inhibitory concentration (IC50). asm.orgresearchgate.neti-base.info This suggests the virus is not simply requiring higher drug concentrations to block entry via unbound CCR5, but is instead gaining the ability to enter via the drug-occupied receptor. asm.orgresearchgate.net The ability to use the drug-bound CCR5 conformation is suggested to correlate with a reduction in MPI. researchgate.netasm.org

Studies have shown that this compound-resistant viruses can exhibit enhanced replication in the presence of the drug, indicating successful adaptation to using the drug-bound CCR5. nih.govnih.gov This adaptation often involves increased reliance on specific regions of CCR5, such as the N-terminus. nih.govnih.govresearchgate.net

Emergence of X4-tropic or Dual/Mixed-tropic Viruses

The emergence of X4-tropic or dual/mixed-tropic viruses is a well-documented escape pathway from CCR5 antagonist therapy. mdpi.comoup.comresearchgate.netnih.govnih.govnatap.orgi-base.infoamanote.com These viruses are not inhibited by this compound because they utilize CXCR4 for entry, either exclusively or in addition to CCR5. natap.org In clinical trials of this compound, the emergence of dual/mixed-tropic or X4 viruses was observed in a proportion of subjects experiencing virological failure. oup.comnih.govnatap.orgi-base.infonatap.orgaidsmap.com

The prevalence of tropism switching can vary, and in some studies, it was not the dominant mechanism of failure. oup.comnih.gov However, the presence of pre-existing minor populations of X4-using variants at baseline can be a significant factor in the emergence of these viruses under CCR5 antagonist pressure. portlandpress.com Studies have shown that even small populations of non-R5 strains present before treatment can be selected for when the R5 population is suppressed by the drug. portlandpress.com

Data from clinical trials indicate that the emergence of dual/mixed or X4 virus can occur relatively early during treatment and does not always coincide precisely with virological failure. aidsmap.com The likelihood of tropism switch might also be influenced by the this compound dose. natap.orgi-base.info

Genetic Determinants of Tropism Shift

The shift in viral tropism from CCR5 to CXCR4 usage is primarily determined by changes in the HIV-1 envelope protein, particularly within the V3 loop of gp120. mdpi.comnih.gov The V3 loop sequence is a key predictor of coreceptor usage. mdpi.com

Mutations in the V3 loop can alter the coreceptor specificity of the virus, enabling it to utilize CXCR4. mdpi.com As few as two amino acid changes in the V3 loop have been shown to change coreceptor specificity from CCR5 to CXCR4. mdpi.com While the V3 loop is the primary determinant, other regions of gp120, such as V1 and V2, and even C2, have also been implicated in influencing coreceptor usage and tropism shifts. mdpi.comresearchgate.netnih.gov

Genotypic analysis of viruses that undergo tropism switching often reveals specific amino acid changes in the V3 loop and potentially other envelope regions that are associated with the ability to use CXCR4. oup.comnih.govresearchgate.net These genetic determinants facilitate the virus's ability to bind to and enter cells via the CXCR4 coreceptor, providing an escape route from this compound inhibition.

Table 1: Summary of Mechanisms of this compound Resistance

Table 2: Examples of V3 Loop Mutations Associated with this compound Resistance

Comparison with Maraviroc and Other Agents (e.g., TAK779, SCH-C, Aplaviroc)

This compound and maraviroc are both small-molecule CCR5 antagonists that bind to similar sites on the CCR5 receptor, inducing conformational changes that prevent gp120 binding. asm.orgwikipedia.orgnih.gov However, their binding interactions can be subtly different, leading to varied cross-resistance profiles. researchgate.netnatap.org

Studies have shown that viruses resistant to maraviroc can remain sensitive to this compound and aplaviroc. researchgate.netnih.govoup.com Conversely, this compound-resistant strains have demonstrated cross-resistance to TAK779 and SCH-C, suggesting shared interaction sites or similar allosteric changes induced in the CCR5 receptor by these compounds. asm.orgnih.govoup.comasm.org For instance, a this compound-resistant virus from a subject in a clinical study showed cross-resistance to TAK779. asm.orgnih.gov

The mechanism of resistance, specifically whether the virus primarily utilizes the N-terminus or requires both the N-terminus and extracellular loops (ECLs) of CCR5 for entry in the presence of the drug, appears to influence the breadth of cross-resistance. researchgate.netnih.gov Viruses that predominantly utilize the N-terminus may exhibit broad cross-resistance, while those requiring both N-terminus and antagonist-specific ECL changes might show a narrower cross-resistance profile. researchgate.netnih.gov

Some studies have indicated that this compound-resistant viruses may not have amino acid changes in the V3 region, unlike resistance to other CCR5 antagonists like SCH-C. asm.org However, other research highlights the importance of V3 loop mutations in conferring this compound resistance. asm.orgnih.govcore.ac.uki-base.info The specific mutations associated with resistance can vary depending on the HIV-1 subtype and the environmental context. asm.orgcore.ac.uk

The following table summarizes some observed cross-resistance patterns among CCR5 antagonists:

Note: This table reflects observed patterns in specific studies and may not be exhaustive or universally applicable to all viral isolates.

Homology Modeling of CCR5 Receptor Structure

Homology modeling has been widely used to generate three-dimensional structures of the CCR5 receptor. This technique relies on the known experimental structures of homologous proteins, such as other chemokine receptors or rhodopsin, as templates. Early models of CCR5 were often based on the bovine rhodopsin structure. plos.orgnih.gov More recent studies have utilized templates with higher sequence identity and resolution, such as the crystal structure of CXCR4 (PDB code: 3ODU). plos.orgnih.govmdpi.comnatap.org These homology models provide a structural framework for understanding the arrangement of the transmembrane helices and extracellular loops that form the binding pocket.

Docking Studies of this compound into CCR5 Binding Pocket

Molecular docking studies are employed to predict the preferred orientation and binding pose of this compound within the CCR5 binding pocket. These studies aim to determine the key residues involved in the interaction and the types of forces that stabilize the complex. This compound is known to bind to a hydrophobic pocket located between the transmembrane helices near the extracellular surface of the CCR5 receptor. wikipedia.orgasm.orgnih.gov

Docking simulations have predicted specific interactions between this compound and residues within this pocket. For instance, the trifluoromethyl phenyl group of this compound may engage in hydrophobic interactions with residues like I198 on transmembrane helix 5 (TM5). wikipedia.org Electrostatic interactions have also been predicted, such as a salt bridge between the positively charged tertiary nitrogen of this compound and the hydrophilic region containing E283 on TM7. plos.orgwikipedia.orgcapes.gov.br Other residues potentially involved in this compound binding include W86 (TM2), Y251 (TM6), and possibly Y108 (TM3), although interactions with Y108 may differ compared to other CCR5 antagonists like maraviroc. asm.org Docking studies with this compound and other CCR5 antagonists like maraviroc, SCH-C, and TAK779 have helped to delineate the nature of the CCR5 binding pocket and the unique interaction profiles of different antagonists. plos.orgcapes.gov.br

Molecular Dynamics Simulations

Molecular dynamics (MD) simulations are used to study the dynamic behavior of the CCR5-vicriviroc complex over time. These simulations provide insights beyond static docking poses, allowing researchers to assess the stability of the binding complex, the conformational changes induced in the receptor upon ligand binding, and the flexibility of the binding pocket. nih.govmdpi.comresearchgate.netscirp.orgrsc.orgtandfonline.commdpi.comnih.gov MD simulations can refine homology models and provide a more realistic representation of the protein-ligand interactions in a membrane environment. nih.govoup.com Analysis of MD trajectories can reveal the persistence of key interactions identified in docking studies and identify additional transient interactions that contribute to binding affinity and receptor modulation. rsc.orgtandfonline.com