In-silico profiling and structural insights into the impact of nSNPs in the P. falciparum acetyl-CoA transporter gene to understand the mechanism of drug resistance in malaria

Abstract

The continuous emergence of resistance to the available drugs poses major constraints in the development of effective therapeutics against malaria. Malaria drug resistance has been attributed to be the manifestation of numerous factors. For example, mutations in the parasite transporter protein acetyl-CoA transporter (Pfact) can remarkably affect its uptake affinity for a drug molecule against malaria, and hence enhance its susceptibility to resistance. To identify major contributors to its loss of functionality, we have thoroughly scrutinized eight such recently reported resistant mutants, via in-silico tools in terms of alterations in different properties. We performed molecular dynamics simulations of the selected Pfact mutants to gain deeper insights into the structural perturbation and dynamicity. Comparison of residue interaction network map of mutants with that of Wild type (WT) protein suggests structural changes as a result of the mutation(s) that translate into the weakening of intra-protein interactions, especially around the drug binding pocket. This, in turn, diminishes the affinity of drug molecules towards the binding site, which was validated by docking analysis. Finally, collating all the observations, we have delineated R108K mutant to deviate the most from WT protein, which, intriguingly suggests that replacing an amino acid with another of similar nature can even translate into greater functional effects as those with dissimilar substitutions.

Communicated by Ramaswamy H. Sarma

Keywords:

• Malaria
• drug resistance
• transporter protein
• molecular dynamics simulations
• docking
• In-silico profiling

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was financially supported by the Department of Biotechnology (DBT), Government of India, grants BT/PR6963/BID/7/427/2012 and BT/BI/25/066/2012, awarded to D.G. Senior Research Fellowship from ICMR is acknowledged by R.S.