Deciphering the competitive inhibition of dihydropteroate synthase by 8 marcaptoguanine analogs: enhanced potency in phenylsulfonyl fragments

Abstract

The emergence of sulfa-drug resistance and reduced efficacy of pterin-based analogs towards Dihydropteroate synthase (DHPS) inhibition dictate a pressing need of developing novel antimicrobial agents for immune-compromised patients. Recently, a series of 8-Marcaptoguanin (8-MG) derivatives synthesized for 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (experimental K_D ∼ 100–.0.36) showed remarkable homology with the pteroic-acid and serve as a template for product antagonism in DHPS. The present work integrates ligand-based drug discovery techniques with structure-based docking, enhanced MD simulation, and MM/PBSA techniques to demonstrate the essential features of 8-MG analogs which make it a potent inhibitor for DHPS. The delicate balance in hydrophilic, hydrophobic substitutions on the 8-MG core is the crucial signature for DHPS inhibition. It is found that the dynamic interactions of active compounds are mainly dominated by consistent hydrogen bonding network with Asp 96, Asn 115, Asp 185, Ser 222, Arg 255 and π-π stacking, π-cation interactions with Phe 190, Lys 221. Further, two new 8-MG compounds containing N-phenylacetamide (compound S1, ΔG_bind-eff = –62.03 kJ/mol) and phenylsulfonyl (compound S3, ΔG_bind-eff = −71.29 kJ/mol) fragments were found to be the most potent inhibitor of DHPS, which stabilize the flexible pABA binding loop, thereby increasing their binding affinity. MM/PBSA calculation shows electrostatic energy contribution to be the principal component in stabilizing the inhibitors in the binding pocket. This fact is further confirmed by the higher energy barrier obtained in umbrella sampling for this class of inhibitors.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Dihydropteroate synthase
• 8-marcaptoguanine
• phenylsulfonyl fragment
• molecular dynamics simulation
• umbrella sampling

Acknowledgments

Funding from DST, SERB (CRG/2019/000578) is highly acknowledged. BKD acknowledges NITK for SRF. The authors would like to thank Miss Pushyaraga P.V. for her timely help and discussion in manuscript preparation. We would also like to thank the Department of Chemistry, NITK Surathkal for their constant support.

Disclosure statement

The authors have declared no conflict of interest.

Data and software availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Additional information

Funding

Funding from DST, SERB (CRG/2019/000578) is highly acknowledged. BKD acknowledges NITK for SRF. The authors would like to thank Miss Pushyaraga P.V. for her timely help and discussion in manuscript preparation. We would also like to thank the Department of Chemistry, NITK Surathkal for their constant support.