Structural Insights from Binding Poses of CCR2 and CCR5 with Clinically Important Antagonists: A Combined In Silico Study

Kothandan, Gugan; Gadhe, Changdev G.; Cho, Seung Joo

doi:10.1371/journal.pone.0032864

Cited by 47 publications

(34 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, we compared the binding sites of CCR2 and CCR5 to facilitate the development of dual antagonists targeting both CCR2 and CCR5. 58 In the present study, we found that Ser101 is important for CCR2 antagonism from our initial rigid docking study. However, the dynamic process showed that 4AAC derivative moved away from Ser101 and the hydrogen bond vanished.…”

Section: Discussionsupporting

confidence: 49%

See 1 more Smart Citation

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

Kothandan¹,

Gadhe²,

Cho³

2013

Bulletin of the Korean Chemical Society

Self Cite

View full text Add to dashboard Cite

Chemokine receptor (CCR2) is a G protein-coupled receptor that contains seven transmembrane helices. Recent pharmaceutical research has focused on the antagonism of CCR2 and candidate drugs are currently undergoing clinical studies for the treatment of diseases like arthritis, multiple sclerosis, and type 2 diabetes. In this study, we analyzed the time dependent behavior of CCR2 docked with a potent 4-azetidinyl-1-arylcyclohexane (4AAC) derivative using molecular dynamics simulations (MDS) for 20 nanoseconds (ns). Homology modeling of CCR2 was performed and the 4AAC derivative was docked into this binding site. The docked model of selected conformations was then utilized to study the dynamic behavior of the 4AAC enzyme complexes inside lipid membrane. MDS of CCR2-16b of 4AAC complexes allowed us to refine the system since binding of an inhibitor to a receptor is a dynamic process and identify stable structures and better binding modes. Structure activity relationships (SAR) for 4AAC derivatives were investigated and reasons for the activities were determined. Probable binding pose for some CCR2 antagonists were determined from the perspectives of binding site. Initial modeling showed that Tyr49, Trp98, Ser101, Glu291, and additional residues are crucial for 4AAC binding, but MDS analysis showed that Ser101 may not be vital. 4AAC moved away from Ser101 and the hydrogen bonding between 4AAC and Ser101 vanished. The results of this study provide useful information regarding the structure-based drug design of CCR2 antagonists and additionally suggest key residues for further study by mutagenesis.

show abstract

Section: Discussionsupporting

confidence: 49%

“…25,[58][59][60][61] In particular, we have developed 3D-QSAR models for CCR2 using ligand based and receptor guided methodologies. 25 In this study, we used Teijin derivatives 23 to derive CoMFA and CoMSIA models, and we found that Ala102 and Asn207 are probably crucial for activity.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

Kothandan¹,

Gadhe²,

Cho³

2013

Bulletin of the Korean Chemical Society

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have been working on GPCR's using in silico methodologies [34][35][36] and we moved our focus on NOPR. Previously there were reports on homology modeling of NOPR.…”

Section: Discussionmentioning

confidence: 99%

The nociceptin receptor (NOPR) and its interaction with clinically important agonist molecules: a membrane molecular dynamics simulation study

et al. 2014

Self Cite

View full text Add to dashboard Cite

The nociceptin receptor (NOPR) is an orphan G protein-coupled receptor that contains seven transmembrane helices. NOPR has a distinct mechanism of activation, though it shares a significant homology with other opioid receptors. Previously there have been reports on homology modeling of NOPR and also molecular dynamics simulation studies for a short period. Recently the crystal structure of NOPR was reported. In this study, we analyzed the time dependent behavior of NOPR docked with clinically important agonist molecules such as NOP (natural agonist) peptide and compound 10 (SCH-221510 derivative) using molecular dynamics simulations (MDS) for 100 ns. Molecular dynamics simulations of NOPR-agonist complexes allowed us to refine the system and to also identify stable structures with better binding modes. Structure activity relationships (SAR) for SCH221510 derivatives were investigated and reasons for the activities of these derivatives were determined. Our molecular dynamics trajectory analysis of NOPR-peptide and NOPR-compound 10 complexes found residues to be crucial for binding. Mutagenesis studies on the residues identified from our analysis could prove useful. Our results could also provide useful information in the structure-based drug design of novel and potent agonists targeting NOPR.

show abstract

“…This motif is situated at the 3 0 end of second external loop. In Human, this particular CCR5 region was found to provide binding pockets for a variety of chemokine agonists and antagonists (Rucker et al 1997, Vassart et al 1996Samson Samson et al 1997;Paterlini 2002;Kothandan et al 2012). Residues at positions 194 and 198 of CCR5 have been associated with lentivirus interactions, such as HIV (Ribeiro et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Adaptive Gene Loss? Tracing Back the Pseudogenization of the Rabbit CCL8 Chemokine

et al. 2016

View full text Add to dashboard Cite

Studies of the process of pseudogenization have widened our understanding of adaptive evolutionary change. In Rabbit, an alteration at the second extra-cellular loop of the CCR5 chemokine receptor was found to be associated with the pseudogenization of one of its prime ligands, the chemokine CCL8. This relationship has raised questions about the existence of a causal link between both events, which would imply adaptive gene loss. This hypothesis is evaluated here by tracing back the history of the genetic modifications underlying the chemokine pseudogenization. The obtained data indicate that mutations at receptor and ligand genes occurred after the lineage split of New World Leporids versus Old World Leporids and prior to the generic split of the of Old World species studied, which occurred an estimated 8-9 million years ago. More important, they revealed the emergence, before this zoographical split, of a "slippery" nucleotide motif (CCCCGGG) at the 3' region of CCL8-exon2. Such motives are liable of generating +1G or -1G frameshifts, which could, however, be overcome by "translesion" synthesis or somatic reversion. The CCL8 pseudogenization in the Old World lineage was apparently initiated by three synapomorphic point mutations at the exon2-intron2 boundary which provide at short range premature terminating codons, independently of the reading frame imposed by the slippery motif. The presence of this motif in New World Leporids might allow verifying this scenario. The importance of CCL8-CCR5 signaling in parasite-host interaction would suggest that the CCL8 knock-out in Old World populations might be related to changes in pathogenic environment.

show abstract

Structural Insights from Binding Poses of CCR2 and CCR5 with Clinically Important Antagonists: A Combined In Silico Study

Cited by 47 publications

References 69 publications

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

Investigation of the Binding Site of CCR2 using 4-Azetidinyl-1-aryl-cyclohexane Derivatives: A Membrane Modeling and Molecular Dynamics Study

The nociceptin receptor (NOPR) and its interaction with clinically important agonist molecules: a membrane molecular dynamics simulation study

Adaptive Gene Loss? Tracing Back the Pseudogenization of the Rabbit CCL8 Chemokine

Contact Info

Product

Resources

About