Molecular docking and dynamics studies on novel benzene sulfonamide substituted pyrazole-pyrazoline analogues as potent inhibitors of Plasmodium falciparum Histo aspartic protease

Abstract

Malaria is the major health issue in African, Asian and Mediterranean regions of the world. Due to the emerging resistance by the parasites and mosquitoes for the current medications and insecticides, respectively, the malaria free human world can be attained only by the novel design and development of new anti-malarial drugs. Hence, we attempted to carry out in silico screening of benzene sulfonamide substituted pyrazole-pyrazoline series against Histo aspartic protease. Our results reveal that the 65% of the data set with the free binding energy in the range of –11.58 to –11.21 kcal/mol, which is categorized as ‘high scoring’. Ligands are docked with the catalytic residues Asp 215, Ser 75, Thr 33 and Ala 217, respectively. Molecular dynamic simulation study of free enzyme and the enzyme complex with 4-(5-(4-methoxyphenyl)-1’phenyl-3’-(p-tolyl)-3,4-1’H,2H-[3,4’-bipyrazol]-2-yl)benezenesulfonamide indicated structural stability. The trajectory analysis of complex reveals that the HAP–ligand complex is more stable than the free HAP. We are of the opinion that our results will be useful for designing potential anti-malarial compounds.

Abbreviations
ADT	=	auto dock tools
BSPP	=	benzene sulfonamide substituted pyrazole-pyrazoline
CQ	=	chloroquine
HAP	=	histo aspartic protease
K	=	Kelvin
MD	=	molecular docking
MM/PBSA	=	molecular mechanics/Poisson Boltzmann surface area
NVT	=	normal volume and temperature
NPT	=	normal pressure and temperature
Ns	=	nanoseconds
PDB	=	protein data bank
.pdb	=	program data base format
P. falciparum	=	Plasmodium falciparum
Ps	=	picoseconds
PMs	=	plasmepsins
P. vivax	=	Plasmodium vivax
Rg	=	radius of gyration
RMSD	=	root mean square deviation
RMSF	=	root mean square fluctuation
WHO	=	World Health Organization

Communicated by Ramaswamy H. Sarma

Keywords:

• Malaria
• HAP
• MM/PBSA
• MD simulation
• P. falciparum
• pyrazole-pyrazoline compounds
• benzene sulfonamide derivatives

Acknowledgements

The authors thank the management of VIT for providing the necessary facilities to carry out this research project.

Disclosure statement

The authors declare that there are no conflicts of interest.

Additional information

Funding

AA and SR gratefully acknowledge the Indian Council of Medical Research (ICMR), Government of India Agency for the research Grant (IRIS ID:2019-0810) [ISRM/12(30)2019]. MT heartfully thanks the ICMR, for the grant of research associateship (IRIS ID:2017-10050).