Protein target similarity is positive predictor of in vitro antipathogenic activity: a drug repurposing strategy for Plasmodium falciparum.

Autor: Mogire RM; Center for Research On Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. reaganmoseti@gmail.com.; Center for Clinical Research, Kenya Medical Research Institute (KEMRI), P. O. Box 54, Kisumu, 40100, Kenya. reaganmoseti@gmail.com.; Center for Research in Therapeutic Sciences, Strathmore University, P.O. Box 59857-00200, Nairobi, Kenya. reaganmoseti@gmail.com., Miruka SA; Center for Clinical Research, Kenya Medical Research Institute (KEMRI), P. O. Box 54, Kisumu, 40100, Kenya.; Center for Research in Therapeutic Sciences, Strathmore University, P.O. Box 59857-00200, Nairobi, Kenya., Juma DW; Center for Clinical Research, Kenya Medical Research Institute (KEMRI), P. O. Box 54, Kisumu, 40100, Kenya.; Department of Emerging Infections Diseases (DEID), Walter Reed Army Institute of Research - Africa, Kisumu, Kenya., McNamara CW; Calibr-Skaggs Institute for Innovative Medicine, a division of The Scripps Research Institute, La Jolla, CA, USA., Andagalu B; Center for Clinical Research, Kenya Medical Research Institute (KEMRI), P. O. Box 54, Kisumu, 40100, Kenya., Burrows JN; Medicines for Malaria Venture, Geneva, Switzerland., Chenu E; Medicines for Malaria Venture, Geneva, Switzerland., Duffy J; Medicines for Malaria Venture, Geneva, Switzerland., Ogutu BR; Center for Clinical Research, Kenya Medical Research Institute (KEMRI), P. O. Box 54, Kisumu, 40100, Kenya.; Center for Research in Therapeutic Sciences, Strathmore University, P.O. Box 59857-00200, Nairobi, Kenya., Akala HM; Center for Clinical Research, Kenya Medical Research Institute (KEMRI), P. O. Box 54, Kisumu, 40100, Kenya. hoseaakala@yahoo.com.; Center for Research in Therapeutic Sciences, Strathmore University, P.O. Box 59857-00200, Nairobi, Kenya. hoseaakala@yahoo.com.; Department of Emerging Infections Diseases (DEID), Walter Reed Army Institute of Research - Africa, Kisumu, Kenya. hoseaakala@yahoo.com.
Jazyk: angličtina
Zdroj: Journal of cheminformatics [J Cheminform] 2024 May 30; Vol. 16 (1), pp. 63. Date of Electronic Publication: 2024 May 30.
DOI: 10.1186/s13321-024-00856-7
Abstrakt: Drug discovery is an intricate and costly process. Repurposing existing drugs and active compounds offers a viable pathway to develop new therapies for various diseases. By leveraging publicly available biomedical information, it is possible to predict compounds' activity and identify their potential targets across diverse organisms. In this study, we aimed to assess the antiplasmodial activity of compounds from the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library using in vitro and bioinformatics approaches. We assessed the in vitro antiplasmodial activity of the compounds using blood-stage and liver-stage drug susceptibility assays. We used protein sequences of known targets of the ReFRAME compounds with high antiplasmodial activity (EC 50  < 10 uM) to conduct a protein-pairwise search to identify similar Plasmodium falciparum 3D7 proteins (from PlasmoDB) using NCBI protein BLAST. We further assessed the association between the compounds' in vitro antiplasmodial activity and level of similarity between their known and predicted P. falciparum target proteins using simple linear regression analyses. BLAST analyses revealed 735 P. falciparum proteins that were similar to the 226 known protein targets associated with the ReFRAME compounds. Antiplasmodial activity of the compounds was positively associated with the degree of similarity between the compounds' known targets and predicted P. falciparum protein targets (percentage identity, E value, and bit score), the number of the predicted P. falciparum targets, and their respective mutagenesis index and fitness scores (R 2 between 0.066 and 0.92, P < 0.05). Compounds predicted to target essential P. falciparum proteins or those with a druggability index of 1 showed the highest antiplasmodial activity.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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