Limits...
Discovery of a selective, safe and novel anti-malarial compound with activity against chloroquine resistant strain of Plasmodium falciparum.

Agarwal A, Paliwal S, Mishra R, Sharma S, Kumar Dwivedi A, Tripathi R, Gunjan S - Sci Rep (2015)

Bottom Line: A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database.This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski's violation.The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Banasthali University, Rajasthan, 304022, India.

ABSTRACT
In recent years the DNA minor groove has attracted much attention for the development of anti-malarial agents. In view of this we have attempted to discover novel DNA minor groove binders through in-silico and in-vitro workflow. A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database. This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski's violation. Finally two compounds NSC639017 and NSC371488 were evaluated for their in-vitro anti-malarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains by SYBR green-I based fluorescence assay. The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

No MeSH data available.


Related in: MedlinePlus

(a) Pharmacophore mapping of the most active test set compound 13b, (b) Pharmacophore mapping of the least active test set compound 23a.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4561909&req=5

f2: (a) Pharmacophore mapping of the most active test set compound 13b, (b) Pharmacophore mapping of the least active test set compound 23a.

Mentions: Activity prediction and pharmacophore mapping of 23 test set compounds was carried out with an objective to verify whether generated pharmacophore model is capable of predicting the activities of compounds not included in training set and classifying them correctly as actives or inactives. A squared correlation coefficient value of 0.81 (Supplementary Figure S1) between actual and estimated activities of the test set clearly demonstrated good prediction ability of the pharmacophore model. During mapping of the test set compounds it was observed that most active compound 13b (Fig. 2a) mapped all four features of the pharmacopore with a fit value of 7.53 (IC50 0.012 μM), whereas least active compound 23a (IC50 10.4 μM) showed a fit value of 5.36 and missed one PI feature (Fig. 2b).


Discovery of a selective, safe and novel anti-malarial compound with activity against chloroquine resistant strain of Plasmodium falciparum.

Agarwal A, Paliwal S, Mishra R, Sharma S, Kumar Dwivedi A, Tripathi R, Gunjan S - Sci Rep (2015)

(a) Pharmacophore mapping of the most active test set compound 13b, (b) Pharmacophore mapping of the least active test set compound 23a.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561909&req=5

f2: (a) Pharmacophore mapping of the most active test set compound 13b, (b) Pharmacophore mapping of the least active test set compound 23a.
Mentions: Activity prediction and pharmacophore mapping of 23 test set compounds was carried out with an objective to verify whether generated pharmacophore model is capable of predicting the activities of compounds not included in training set and classifying them correctly as actives or inactives. A squared correlation coefficient value of 0.81 (Supplementary Figure S1) between actual and estimated activities of the test set clearly demonstrated good prediction ability of the pharmacophore model. During mapping of the test set compounds it was observed that most active compound 13b (Fig. 2a) mapped all four features of the pharmacopore with a fit value of 7.53 (IC50 0.012 μM), whereas least active compound 23a (IC50 10.4 μM) showed a fit value of 5.36 and missed one PI feature (Fig. 2b).

Bottom Line: A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database.This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski's violation.The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Banasthali University, Rajasthan, 304022, India.

ABSTRACT
In recent years the DNA minor groove has attracted much attention for the development of anti-malarial agents. In view of this we have attempted to discover novel DNA minor groove binders through in-silico and in-vitro workflow. A rigorously validated pharmacophore model comprising of two positive ionizable (PI), one hydrophobic (HY) and one ring aromatic (RA) features was used to mine NCI chemical compound database. This led to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski's violation. Finally two compounds NSC639017 and NSC371488 were evaluated for their in-vitro anti-malarial activities against Plasmodium falciparum 3D7 (CQ sensitive) and K1 (CQ resistant) strains by SYBR green-I based fluorescence assay. The results revealed that out of two, NSC639017 posses excellent anti-malarial activity particularly against chloroquine resistant strain and moreover NSC639017 also appeared to be safe (CC50 126.04 μg/ml) and selective during cytotoxicity evaluation.

No MeSH data available.


Related in: MedlinePlus