In silico identification of natural products as novel ligands for the human drd1 receptor

Abstract

A host of central neuropathic conditions stems from dysfunction in dopaminergic neurotransmission. The choice treatment for such dysfunctions is the use of drugs that target dopamine (DA) receptors, a subgroup of G protein-coupled receptors (GPCR). Majority of DA receptors within the central nervous system is dopamine receptor D1 (DRD1). At present, there is scarcity of clinically useful DRD1 ligands and unintended effects may occur such as extrapyramidal side effects due to non-specific interaction of the drug with other DA receptors. A promising source of such ligands are natural products (NPs) which have rich functionalities, high potency and selectivity when optimized as drugs. However, there have been few studies that explore NPs as potential ligands for DA receptors. The study identifies primary NP analogs of DA as potential DRD1 ligands by analyzing and interpreting protein-ligand interactions via molecular docking analysis and pharmacophore modeling. The protein-ligand complexes are generated with the use of homology models by Feng, et al. (2012). Analysis of pharmacophore model is performed in relation to the top intrasubtype hit, ZINC 14649954 (perrotettin F). The results of the study suggest that perrotettin F is a potential ligand of the human DRD1 receptor due to its higher affinity to DRD1 relative to the reference ligands. Experimental functional assays are recommended to further validate these findings. The results of the study contributes information for the improvement of binding affinity of potential DA drugs to DA receptors via structure-guided optimization. It also contributes to the existing knowledge on the potential of NPs as ligands for GPCRs