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Research Article

A computational perspective towards the identification of promising lead molecules against 6-hydroxy-methyl dihydropterin pyrophosphokinase (HPPK) from Acinetobacter baumannii

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Received 01 Apr 2023, Accepted 17 Jul 2023, Published online: 25 Jul 2023
 

Abstract

Acinetobacter baumannii is an ESKAPE pathogen that causes endocarditis, pneumonia, blood infections, urinary tract infections, and several other illnesses. In addition, it is mainly responsible for nosocomial infection-related mortality. Gram-negative A. baumannii bacterium (AYE Strain) has high MDR and XDR levels. Due to its function in synthesizing purines and amino acids, folic acid is a significant molecule necessary for the growth of bacteria. The metabolic pathway of folate production is therefore a potential therapeutic target to inhibit bacterial growth. In the current study, the three-dimensional model of 6-Hydroxy-methyl dihydropterinpyrophosphokinase (HPPK) was predicted and subsequently processed through a virtual high throughput screening (vHTS) against compounds from Enamine HTSC library, that could bind to its active site. Three lead candidates (Z73322064, Z354558542, and Z906123504) and a control molecule (7,8 dihydro-7,7-dimethyl-6-hydroxymethlypterin; Accession Number: DB02278) were identified using several screening criteria namely estimated binding affinity, estimated inhibition constant, drug-like properties, ADME properties, mode of binding, and interaction patterns of the screened compounds. The physiological behavior of ligand binding on the HPPK enzyme was then studied using molecular dynamics simulations of apo and ligand bound complexes. This study proposed the following three molecules: Z73322064, Z354338542, and Z906123504 as promising lead candidates against the substrate-binding site of the HPPK enzyme from A. baumannii using global, essential dynamics studies along with MM/PBSA based binding free energy analysis.

Communicated by Ramaswamy H. Sarma

Acknowledgements

Dr. Amit Kumar Singh thanks Indian Council of Medical Research (ICMR) and Indian National Science Academy (INSA), New Delhi, India. Mr. Saurabh Kumar Bhati thanks Council of Scientific and Industrial Research (CSIR) for providing Senior Research Fellowship. The authors thank Sharda University for support. The authors thank Sharda University, Greater Noida, India for support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

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