PMID- 29383457 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 1758-2946 (Print) IS - 1758-2946 (Electronic) IS - 1758-2946 (Linking) VI - 10 IP - 1 DP - 2018 Jan 30 TI - Adverse drug reactions triggered by the common HLA-B*57:01 variant: virtual screening of DrugBank using 3D molecular docking. PG - 3 LID - 10.1186/s13321-018-0257-z [doi] LID - 3 AB - BACKGROUND: Idiosyncratic adverse drug reactions have been linked to a drug's ability to bind with a human leukocyte antigen (HLA) protein. However, due to the thousands of HLA variants and limited structural data for drug-HLA complexes, predicting a specific drug-HLA combination represents a significant challenge. Recently, we investigated the binding mode of abacavir with the HLA-B*57:01 variant using molecular docking. Herein, we developed a new ensemble screening workflow involving three X-ray crystal derived docking procedures to screen the DrugBank database and identify potentially HLA-B*57:01 liable drugs. Then, we compared our workflow's performance with another model recently developed by Metushi et al., which proposed seven in silico HLA-B*57:01 actives, but were later found to be experimentally inactive. METHODS: After curation, there were over 6000 approved and experimental drugs remaining in DrugBank for docking using Schrodinger's GLIDE SP and XP scoring functions. Docking was performed with our new consensus-like ensemble workflow, relying on three different X-ray crystals (3VRI, 3VRJ, and 3UPR) in presence and absence of co-binding peptides. The binding modes of HLA-B*57:01 hit compounds for all three peptides were further explored using 3D interaction fingerprints and hierarchical clustering. RESULTS: The screening resulted in 22 hit compounds forecasted to bind HLA-B*57:01 in all docking conditions (SP and XP with and without peptides P1, P2, and P3). These 22 compounds afforded 2D-Tanimoto similarities being less than 0.6 when compared to the structure of native abacavir, whereas their 3D binding mode similarities varied in a broader range (0.2-0.8). Hierarchical clustering using a Ward Linkage revealed different clustering patterns for each co-binding peptide. When we docked Metushi et al.'s seven proposed hits using our workflow, our screening platform identified six out of seven as being inactive. Molecular dynamic simulations were used to explore the stability of abacavir and acyclovir in complex with peptide P3. CONCLUSIONS: This study reports on the extensive docking of the DrugBank database and the 22 HLA-B*57:01 liable candidates we identified. Importantly, comparisons between this study and the one by Metushi et al. highlighted new critical and complementary knowledge for the development of future HLA-specific in silico models. FAU - Van Den Driessche, George AU - Van Den Driessche G AUID- ORCID: 0000-0003-2939-8828 AD - Department of Chemistry, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA. FAU - Fourches, Denis AU - Fourches D AUID- ORCID: 0000-0001-5642-8303 AD - Department of Chemistry, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA. dfourch@ncsu.edu. LA - eng PT - Journal Article DEP - 20180130 PL - England TA - J Cheminform JT - Journal of cheminformatics JID - 101516718 PMC - PMC5790764 OTO - NOTNLM OT - ADR OT - Abacavir OT - DrugBank OT - HLA OT - HLA-B*57:01 OT - Molecular docking OT - Virtual screening EDAT- 2018/02/01 06:00 MHDA- 2018/02/01 06:01 PMCR- 2018/01/30 CRDT- 2018/02/01 06:00 PHST- 2017/07/14 00:00 [received] PHST- 2018/01/17 00:00 [accepted] PHST- 2018/02/01 06:00 [entrez] PHST- 2018/02/01 06:00 [pubmed] PHST- 2018/02/01 06:01 [medline] PHST- 2018/01/30 00:00 [pmc-release] AID - 10.1186/s13321-018-0257-z [pii] AID - 257 [pii] AID - 10.1186/s13321-018-0257-z [doi] PST - epublish SO - J Cheminform. 2018 Jan 30;10(1):3. doi: 10.1186/s13321-018-0257-z.