1. developed since 1960’s, and the interest

1. IntroductionThe relationship between ligand and protein receptor hadbeen previously focused around the idea of lock-and-key mechanism, with a poolof stereospecific and independent sites present on a protein species1.

The binding sites on aprotein that are recognised by the receptor’s endogenous agonist are known asorthosteric site. In contrast, allostery describe the interaction of ligandswith binding sites that are topologically away from the orthosteric site. There are two main types of allosteric modulators, in termsof regulation of protein activity: Positive Allosteric Modulators (PAMs) andNegative Allosteric Modulators (NAMs). PAMs enhance activity of orthostericligand’s effect, by enhancing binding or by increasing efficacy of orthostericligand, while NAMs exhibits inhibitory effect. PAMs may also exert agonisticproperties in absence of orthosteric ligand.2 In addition, there are silentallosteric modulators (SAMs), also called neutral allosteric Ligands (NALs)3, binds to an allosteric sitewithout affecting receptor’s functionbut block the functional activity of both PAMs and NAMs.4Evidence has shown that Interest in targeting ligands toGPCR’s allosteric site developed since 1960’s, and the interest has grown thepast decade. May et al.

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suggest such interest may have been motivated by thepharmaceutical industry and the transformation in high-throughput screeningmethods to functional from mainly binding-based. 2ChemoinformaticsChemoinformatics was popularised with the birth of computertechnology in the 1940’s, 1946 is often regarded as the birth year ofchemoinformatics. Chemoinformatics was then flourished with the development ofdatabase systems and improvement of computer technology and 3D drawing.

5 In 1998, Dr. Brown wroteregarding chemoinformatics: “Chemoinformatics is the mixing of informationtechnology and management resources to convert data into information, andinformation into knowledge for the intention of making better decisions quickerin drug lead identification and optimisation. The use of those information hasbecome a critical part of the drug discovery process.” 6 Modern drug discovery process mostly involves highthroughput screening of millions of small molecules from databases againstbiological targets.

Hits are then identified and optimised for greater orbetter selectivity, affinity, efficacy, metabolic stability and oralbioavailability. However, screening fragments can be a tedious and lengthyprocess. There were some allosteric modulators found though high throughputscreening, but the allosteric small molecule hits mainly have unknown chemicalcompositions inappropriate for the discovery of allosteric modulators and alsolow affinities.7 Gianti et.

al proposed astrategy for the creation of libraries of “privileged fragments” that are ableto provide high-quality hits by recognising substructures from databases ofknown drugs to be used as templates. 8   2. Allosteric GPCR modulator: Close to 30 percent of FDA approved drug targets GPCRs, anumber reported by Overington et. al in 2006 9 but there are only twoproduct on the pharmacy shelves that target allosteric binding site- Sensipar cinacalcet-PAM of calcium-sensing receptor, and Maraviroc (Selzentry in the US andCelsentri in the rest of the world)- NAM of CCR5 3 2.

1 Pharmaceutical potential ** Use examples- CRF1, GCGR,M2, P2Y1Allosteric modulators (AM) is gaining interest ofresearchers as it presents itself as a novel approach to drug targeting. AMs havethe advantage of being non-competitive because they bind receptors at a distinctsite and modify receptor function even if the endogenous ligand also is bindingie. at the orthosteric site. Due to this characteristic, AMs behave more like adimmer3, not restricted to justsimply turning a receptor on or off the way most drugs do, instead offeringcontrol over the magnitude of activation or inhibition, while allowing the bodyto hold its natural control over activation of receptor.

3 Due to their capability tochange receptor conformations in the presence of orthosteric ligand, AMs can”fine-tune” classical pharmacological responses. 2 In addition to that, AMs hasshown to have the ability to distinguish between different receptor complexesof GPCRs.10 This ability is significantas it could provide therapeutic benefits through highly precise modulation ofreceptor.Example of a GPCR, M2 receptor is one of thesubtype of the Muscarinic Acetylcholine receptor (mAChR).

M2 mAChR generally serves an inhibitoryfunction on the release of neurotransmitters and is located on the presynapticsite of cholinergic and non-cholinergic neurons11 in the brainstem, hippocampus, striatum,hypothalamus/thalamus and cortex12–14. It has been proposed that enhancingsynaptic ACh concentration by selectively inhibiting M2 autoreceptors may be valuable in thetreatment of Alzheimer’s disease and psychosis15Up until recently,common probe compounds and marketed drugs that target GPCRs are small molecules,for example codeine, but it is also important to know there is an emerginginterest in utilizing biologics and antibodies to target GPCRs as well9,16 2.2 Pharmacological features ** Use examples- CRF1, GCGR,M2, P2Y1GPCR allostericmodulators (AMs) demonstrate one or more of the following pharmacologicalproperties: Efficacy modulation— the allosteric effect can alter intracellular responses, leading to a changein the intrinsic efficacy (the capacity of a drug to initiate a stimulus fromone receptor) of an orthosteric ligand.  Agonists have positive efficacy,inverse agonists have negative efficacy whilst neutral antagonists have zeroefficacy.17Affinitymodulation — the conformational change caused by allosteric binding can poseimpact on either the association and/or dissociation rate of the orthostericbinding pocket.Agonism/ inverseagonism — As discussed, allosteric modulators can have positive effect ornegative effect on receptor signalling, regardless of the presence or absenceof an orthosteric ligand.16 Some examples of allosteric ligands and theirrespective receptors are: LY2119620- M2 18;   MRS2500- P2Y119; CP-376395- CRF1 (Corticotropin releasingfactor 1)20; MK-0893- GCCR (Glucagon receptor)21


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