DAKB-GPCRs: An Integrated Computational Platform for Drug Abuse Related GPCRs

Abstract

Drug abuse (DA) or drug addiction is a complicated brain disorder which is commonly considered as neurobiological impairments caused by both genetic factors and environmental effects. Among DA-related targets, G protein-coupled receptors (GPCRs) play an important role in DA therapy. However, only 52 GPCRs have been published with crystal structures in the recent two decades. In the effort to overcome the limitations of crystal structure and conformational diversity of GPCRs, we built homology models and performed conformational searches by molecular dynamics (MD) simulation. To accelerate and facilitate the drug abuse research, we construct a DA-related GPCR-specific chemogenomics knowledgebase (KB) (DAKB-GPCRs) for its research that can be implemented with our established and novel chemogenomics tools as well as algorithms for data analysis and visualization. Our established TargetHunter and HTDocking tools, as well as our novel tools that include target classification and Spider Plot, are compiled into the platform. Our DAKB-GPCRs provides the following results for a query compound: (1) blood−brain barrier (BBB) plot via our BBB predictor, (2) docking scores via HTDocking, (3) similarity score via TargetHunter, (4) target classification via machine learning methods that utilize both docking scores and similarity scores, and (5) a drug−target interaction network via Spider Plot.

Virus-CKB: an integrated bioinformatics platform and analysis resource for COVID-19 research

“…The Virus-CKB server is an integrated web server that combines our established tools and algorithms (HTDocking [ 18–22 ], TargetHunter [ 23 ], blood–brain barrier (BBB) predictor [ 20–22 ] and Spider Plot [ 18 , 19 , 24 ]) and other third-party software (Open Babel [ 25 ], JSME Molecular Editor [ 26 ], idock [ 27 ] and NGL Viewer [ 28 ]) for target identification and network systems pharmacology analysis. The Virus-CKB pipeline is shown in Figure 1 .…”

“…Compounds with IC50 lower than 1 μM towards a viral-related target were considered as the active ligands, while those larger than 10 μM were regarded as the inactive ones. The detailed protocol for data mining and preparation of drugs and chemicals can be found in our recent publication [ 24 ].…”

“…Users can submit their query compound(s) through JSME Molecular Editor v2017-03-01 [ 26 ]. Virus-CKB was constructed based on our established molecular database prototype DAKB-GPCRs [ 24 ] ( https://www.cbligand.org/dakb-gpcrs/ ) using the same management systems and servers as described previously [ 24 ].…”

“…Then, HTDocking powered by idock [ 27 ] will automatically dock each query compound into the previously defined binding pockets of these different conformations and generate docking scores respectively. More detail about HTDocking can be found in our previous publication [ 24 ].…”

“…CSP-Target Mapping or Spider Plot [ 18 , 19 , 24 ] is also integrated into Virus-CKB for visualizing the molecule–protein interaction network based on the output of HTDocking and TargetHunter. The detailed information related to Spider Plot can found in our recent publication [ 24 ].…”