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.
Highlights
Protocols in association with wet lab experimentation to identify novel and safe Pf DNA minor groove binders with ability to act against resistant strain of P. falciparum
Pharmacophore models with varying number and type of features were generated and evaluated on the basis of cost fuction calculated in bits by HypoGen module[6]
The model showed a difference of 98.79 bits between total cost (149.20) and the null cost
Summary
During mapping of training set compounds it was observed that most active compound 13a (IC50 0.002 μ M) of training set mapped well over the model with a fit value of 8.027. The results of CatScramble clearly shows that the generation of original model is not by chance rather it is an outcome of true correlation between structures of training set compounds and Pf DNA minor groove inhibitory activity. 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.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
