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In silico Screening and Evaluation of Plasmodium falciparum Protein Kinase 5 (PK5) Inhibitors
Author(s) -
Eubanks Amber L.,
Perkins Marisha M.,
Sylvester Kayla,
Ganley Jack G.,
Posfai Dora,
Sanschargrin Paul C.,
Hong Jiyong,
Sliz Piotr,
Derbyshire Emily R.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800625
Subject(s) - in silico , plasmodium falciparum , computational biology , protein kinase a , biology , kinase , malaria , virology , medicine , genetics , immunology , gene
An in silico screen of 350 000 commercially available compounds was conducted with an unbiased approach to identify potential malaria inhibitors that bind to the Plasmodium falciparum protein kinase 5 ( Pf PK5) ATP‐binding site. P f PK5 is a cyclin‐dependent kinase‐like protein with high sequence similarity to human cyclin‐dependent kinase 2 ( Hs CDK2), but its precise role in cell‐cycle regulation remains unclear. After two‐dimensional fingerprinting of the top scoring compounds, 182 candidates were prioritized for biochemical testing based on their structural diversity. Evaluation of these compounds demonstrated that 135 bound to Pf PK5 to a similar degree or better than known Pf PK5 inhibitors, confirming that the library was enriched with Pf PK5‐binding compounds. A previously reported triazolodiamine Hs CDK2 inhibitor and the screening hit 4‐methylumbelliferone were each selected for an analogue study. The results of this study highlight the difficult balance between optimization of Pf PK5 affinity and binding selectivity for Pf PK5 over its closest human homologue Hs CDK2. Our approach enabled the discovery of several new Pf PK5‐binding compounds from a modest screening campaign and revealed the first scaffold to have improved Pf PK5/ Hs CDK2 selectivity. These steps are critical for the development of Pf PK5‐targeting probes for functional studies and antimalarials with decreased risks of host toxicity.