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Integration on Ligand and Structure Based Approaches in GPCRs

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Structure and Function of GPCRs

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 30))

Abstract

The GPCRs are involved in wide range of physiological functions and pathological conditions and hence they are considered drug targets of immense pharmaceutical importance. Modification of the cell-specific signaling and functioning of the GPCRs provides an excellent opportunity for drug design activities. In view of the diverse and complex nature of GPCR signaling, the proper understanding of receptor structure is essential to illustrate their elusive structure–function relationships for rational drug design by the application of efficient and inexpensive molecular modeling techniques. Despite advances in GPCR protein crystallization, the structural information of most GPCRs is still unclear that necessitates the application of homology modeling techniques to derive protein models for structure based drug design. However low sequence similarity in GPCRs coupled with high structural plasticity may hinder the development of appropriate protein models. In order to circumvent the problems, the development of ligand based models integrated with structure based models may converge to an integrated model duly validated on internal and/or external test set models which may be useful in virtual screening for identifying the hits and in generating the focused libraries for prioritizing the molecules for synthesis. The integrated models may also be helpful in increasing our understanding of drug–receptor interactions.

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Abbreviations

(S)-6-OH-DPAT:

(S)-6-hydroxy-2-(dipropylamino)tetralin

(S)-7-OH-DPAT:

(S)-7-hydroxy-2-(dipropylamino)tetralin

(S)-DPAT:

(S)-Dipropylamino tetralin

2-AMC:

2-(Aminomethyl)chromans

2D QSAR:

Two-dimensional quantitative structure–activity relationships

2-OHNPA:

2-Hydroxy-N-n-propylnorapomorphine

3D QSAR:

Three-dimensional quantitative structure–activity relationship

3-PPP:

3-(3-Hydroxyphenyl)-N-n-propylpiperidine

5-OH-DPAT:

5-Hydroxy-2-(dipropylamino)tetralin

7-OH-OHBQ:

7-Hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline

9-OH-OHBQ:

9-Hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline

α1a Adr:

α1a adrenergic receptor

α1b Adr:

α1b adrenergic receptor

α1c Adr:

α1c adrenergic receptor

α2 Adr:

α2 adrenergic receptor

β1 Adr:

β1 adrenergic receptor

β2 Adr:

β2 adrenergic receptor

AAA:

Active analog based approaches

ADTN:

6-Amino-5,6,7,8-tetrahydronaphthalene-2,3-diol

APO:

Apomorphine

Ar:

Aromatic

BPH:

Benign prostate hyperplasia

CADD:

Computer aided drug design

CFP:

Common feature pharmacophore

CHARMm:

Chemistry at HARvard Macromolecular mechanics

CNS:

Central nervous system stimulant

CoMFA:

Comparative molecular field analysis

CoMSIA:

Comparative molecular similarity index analysis

DA:

Dopamine

DHX:

Dihydrexidine

ECL2:

Extracellular loop 2

GIP:

GPCR-interacting protein

Glide XP:

Glide extra precision

GRK:

G protein-coupled receptor kinases

HAl:

Hydrophobic aliphatic

HAr:

Hydrophobic aromatic

HASL:

Hypothetical active site lattice

HBA:

Hydrogen bond acceptor

HBD:

Hydrogen bond donor

HOMO:

Highest occupied molecular orbital

HY:

Hydrophobic

LBDD:

Ligand based drug design

LUMO:

Lowest unoccupied molecular orbital

LUTS:

Low urinary tract symptoms

MDDR:

MDL Drug Data Report

MR:

Molar refractivity

NCE:

Novel chemical entity

NMR:

Nuclear magnetic resonance

NPA:

N-n-propylnorapomorphine

PD:

Parkinson’s disease

PI:

Positive ionizable

RA:

Ring aromatic

RMSD:

Root mean square deviation

SBDD:

Structure based drug design

SSS:

Substituent spanned space

TM:

Transmembrane

VS:

Virtual screening

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  1. Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow, 226 031, India

    Anil K. Saxena

  2. Global Institute of Pharmaceutical Education and Research, Kashipur, Uttarakhand, India

    Shome S. Bhunia

  3. Department of Chemistry, Amity University, Lucknow, India

    Mridula Saxena

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    Guillaume Lebon

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Saxena, A.K., Bhunia, S.S., Saxena, M. (2017). Integration on Ligand and Structure Based Approaches in GPCRs. In: Lebon, G. (eds) Structure and Function of GPCRs. Topics in Medicinal Chemistry, vol 30. Springer, Cham. https://doi.org/10.1007/7355_2016_24

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