Identification of natural compound inhibitors against PfDXR: A hybrid structure-based molecular modeling approach and molecular dynamics simulation studies.

Authors:
Anu Manhas
Anu Manhas
a School of Chemical Sciences
Urbana | United States
Dhaval Patel
Dhaval Patel
National Institutes of Health
United States
Prakash C Jha
Prakash C Jha
Gujarat University
India

J Cell Biochem 2019 Apr 17. Epub 2019 Apr 17.

Centre for Applied Chemistry, Central University of Gujarat, Gandhinagar, Gujarat, India.

In the present contribution, multicomplex-based pharmacophore studies were carried out on the structural proteome of Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase. Among the constructed models, a representative model with complementary features, accountable for the inhibition was used as a primary filter for the screening of database molecules. Auxiliary evaluations of the screened molecules were performed via drug-likeness and molecular docking studies. Subsequently, the stability of the docked inhibitors was envisioned by molecular dynamics simulations, principle component analysis, and molecular mechanics-Poisson-Boltzmann surface area-based free binding energy calculations. The stability assessment of the hits was done by comparing with the reference (beta-substituted fosmidomycin analog, LC5) to prioritize more potent candidates. All the complexes showed stable dynamic behavior while three of them displayed higher binding free energy compared with the reference. The work resulted in the identification of the compounds with diverse scaffolds, which could be used as initial leads for the design of novel PfDXR inhibitors.

Download full-text PDF

Source
https://onlinelibrary.wiley.com/doi/abs/10.1002/jcb.28714
Publisher Site
http://dx.doi.org/10.1002/jcb.28714DOI Listing
April 2019
5 Reads

Publication Analysis

Top Keywords

molecular dynamics
8
molecular
5
analysis molecular
4
molecular mechanics-poisson-boltzmann
4
principle component
4
simulations principle
4
mechanics-poisson-boltzmann surface
4
component analysis
4
surface area-based
4
calculations stability
4
stability assessment
4
assessment hits
4
energy calculations
4
binding energy
4
area-based free
4
free binding
4
dynamics simulations
4
inhibitors envisioned
4
evaluations screened
4
screened molecules
4

References

(Supplied by CrossRef)
Biophysical aspect of phosphatidylinositol 3‐kinase and role of oncogenic mutants (E542K & E545K)
Kalsi N et al.
J Biomol Struct Dyn 2016

Similar Publications