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

Table 2 Association between in vitro antiplasmodial activity of ReFRAME compounds and various factors: parameters of similarity between known–predicted protein target, average number of predicted P. falciparum targets and mutagenesis index score and mutagenesis fitness score of predicted P. falciparum targets

	Blood stage EC₅₀ at 48 h		Blood stage EC₅₀ at 72 h		Liver stage EC₅₀ at 48 h
	Beta (SE)	P value	Beta (SE)	P value	Beta (SE)	P value
BLAST percent similarity	−0.026 (0.003)	< 2.2 × 10^–16	−0.030 (0.002)	< 2.2 × 10^–16	−0.0060 (0.0016)	0.00011
BLAST bit score	−0.14 (0.010)	< 2.2 × 10^–16	−0.14 (0.009)	< 2.2 × 10^–16	−0.040 (0.0064)	6.52 × 10^–10
Percent similarity of functional amino acids	−0.059 (0.007)	< 4.6 × 10^–16	−0.068 (0.007)	< 2.2 × 10^–16	−0.025 (0.0055)	8.17 × 10^–06
Average number of predicted P. falciparum targets^a	0.21 (0.012)	< 2.2 × 10^–16	0.30 (0.011)	< 2.2 × 10^–16	0.0022 (0.0078)	0.78
Mutagenesis index score (MIS)^b	0.035 (0.013)	0.0054	0.041 (0.012)	0.0005	0.020 (0.0081)	0.012
Mutagenesis fitness score (MFS)^c	0.016 (0.0072)	0.026	0.019 (0.0067)	0.0044	0.0074 (0.0046)	0.10

EC₅₀, half maximal effective concentration. Univariate linear regression analyses were performed between drugs in vitro antiplasmodial activity (EC₅₀ at 48 and 72 h) and percent similarity between its known targets and predicted P. falciparum targets (BLAST percent identity and bit score), similarity of functional and structural amino acids and number of predicted P. falciparum targets. EC₅₀s, percentage similarity parameters and bit scores were log transformed to make them normally distributed
SE, standard error
^aAverage number of P. falciparum targets was determined by dividing the total number of predicted P. falciparum targets with the number of known targets for each drug
^bMutagenesis index score (MIS) indicates the comparative essentiality of P. falciparum genes based on the number of recovered CDS insertions relative to the potential number that could be recovered by large-scale mutagenesis [20]
^cThe Mutagenesis Fitness Score (MFS) estimates the relative growth fitness cost for mutating a gene based on its normalized quantitative insertion-site sequencing (QIseq) reads distribution [20]

ISSN: 1758-2946