Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors

Abstract

G-protein coupled receptors (GPCRs) comprise a large superfamily of proteins that are targets for nearly 50% of drugs in clinical use today. In the past, the use of structure-based drug design strategies to develop better drug candidates has been severely hampered due to the absence of the receptor's three-dimensional structure. However, with recent advances in molecular modeling techniques and better computing power, atomic level details of these receptors can be derived from computationally derived molecular models. Using information from these models coupled with experimental evidence, it has become feasible to build receptor pharmacophores. In this study, we demonstrate the use of the Hybrid Structure Based (HSB) method that can be used effectively to screen and identify prospective ligands that bind to GPCRs. Essentially; this multi-step method combines ligand-based methods for building enriched libraries of small molecules and structure-based methods for screening molecules against the GPCR target. The HSB method was validated to identify retinal and its analogues from a random dataset of ∼300,000 molecules. The results from this study showed that the 9 top-ranking molecules are indeed analogues of retinal. The method was also tested to identify analogues of dopamine binding to the dopamine D2 receptor. Six of the ten top-ranking molecules are known analogues of dopamine including a prodrug, while the other thirty-four molecules are currently being tested for their activity against all dopamine receptors. The results from both these test cases have proved that the HSB method provides a realistic solution to bridge the gap between the ever-increasing demand for new drugs to treat psychiatric disorders and the lack of efficient screening methods for GPCRs.

Identification of Novel Scaffolds from an Original Chemical Library as Potential Antipsychotics

“…Even if the traditional handicap of lacking crystal structures of aminergic GPCRs has very recently been partially overcome [8,9], we still depend on the generation of homology-derived models to perform receptor based (RB) VS. ii) The multirreceptorial profile, responsible for the clinical efficacy of this type of drugs, [10] points out that one should in principle screen against a battery of receptors. Nevertheless, other alternative approaches have been proposed for the design of novel scaffolds for GPCR ligands with polipharmacology, which include hybrid structure based method [11], or a proper combination of physicochemical descriptors that characterize the binders of each considered receptor [12].…”

Inhibiting Early-Stage Events in HIV-1 Replication by Small-Molecule Targeting of the HIV-1 Capsid

“…An iterative in silico-in vitro HSB method was employed for screening small molecules that inhibit the formation of the CA NTD-NTD interface (18). The protocol has been described in detail elsewhere (4,27,28).…”

“…Chemical core analysis using clustering and principal-component analysis resulted in 300 molecules that were then docked to the binding site of CA-NTD using the GOLD program (Genetic Optimisation for Ligand Docking, version 4.1) (15). The docked receptor-ligand complexes were then scored using a customizable knowledge-based scoring function that is based on the nature of the interaction of every atom within the NTD-NTD docking pharmacophore (18). A consensus scoring scheme that involves GoldScore, ChemScore, contact score, and a shape-weighted scoring scheme (17) was then used to rank the compounds.…”

“…The availability of atomic-level details of the NTD-NTD inter-face, coupled with mutagenesis studies demonstrating that disruption of this interface is deleterious to the virus, underscores the potential of this site as a target for the design of new HIV-1 inhibitors. In the studies reported here, we used the hybrid structurebased (HSB) screening method (18), which employs both structural and biochemical information, to design inhibitors of the HIV-1 CA NTD-NTD interface. An initial screen identified 4,4=-[dibenzo [b,d]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026) as a promising starting point for design of CA inhibitors that bind to the NTD-NTD interface and interfere with HIV-1 replication at an early, preintegration stage.…”

Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach

“…Hybrid structure based method The HSB protocol, described in detail elsewhere [32], was employed for the virtual screening of nearly 3 million compounds to identify small-molecule inhibitors of T. gondii. The HSB procedure involved 4 major steps, namely: (1) construct a structural model of the T. gondii MTIP; (2) design the 3D pharmacophore based on the key molecular interactions between MyoA and MTIP in the complex; (3) screen the in-house molecular libraries to identify ''hits''; and (4) re-rank the hits using customized molecular docking and scoring schemes.…”