AN UPDATED STATUS OF ALANINE RACEMASE INHIBITORS: A REVIEW
HTML Full TextAN UPDATED STATUS OF ALANINE RACEMASE INHIBITORS: A REVIEW
P. Rathee, S. Saini and A. Khatkar *
Faculty of Pharmaceutical Sciences, B. M. University, Rohtak, Haryana, India.
ABSTRACT: Enzyme Alanine racemase is well known for performing a predominating role in mycobacterium cell wall synthesis. D-alanine provided by Alanine racemase serves as a peptidoglycan precursor, utterly vital for maintaining the growth and integrity of the cell wall. The lipid-rich mycobacterium cell wall is prevalent amidst prokaryotes with immense potential of becoming a therapeutic target for new drug discovery. The imperative role of Alanine racemase in mycobacterium cell wall synthesis implies that its inhibition is of uttermost priority in order to deal with various pathogenic infections. Interference with metabolic processes, lack of specificity, and cellular toxicity caused by several known inhibitors prompted renewed efforts by researchers to discover new and improved inhibitors with better therapeutic indexes. This paper provides an overview of the updated status of reported Alanine racemase inhibitors based on shreds of evidence in literature so that more precise inhibitors could be explored, designed, and identified to rationalize the overall drug discovery process, which will be true serendipity for the mankind.
Keywords: In-situ gel, Acyclovir, Anti-viral, HPMC E50 LV, Pluronic F-127
INTRODUCTION: Microorganisms are defined as infectious agents of microscopic size, including bacteria, fungi, protozoan and viruses, responsible for causing various types of infections. In an attempt to deal with infectious agents, there is an urgent need for an antimicrobial agent that antagonizes the action of infection-causing microbe 1. The discovery of antimicrobial drugs conferred huge benefits on human health and changed the fate of mankind dramatically. Penicillin was the first antibiotic discovered by Alexander Fleming, which proved to be a boon in curing infectious diseases.
As a result, antibiotics were regarded as wonder drugs and used generally for managing infection caused by pathogens. However, a large number of people are reliant on antibiotics for the maintenance and improvement of health. Antibiotics have become one of the most commonly prescribed pharmaceutical drugs for curing various infections. This ultimately leads to the development of drug resistance that may often associate with careless use and overconsumption, which is a key issue of concern for the researchers 2.
Now the greatest challenge of the twenty-first century is the development of drug resistance responsible for causing immense human suffering. The resistance problem urges iterated effort to strive antibacterial agents efficacious against pathogenic bacteria rebellious to commercial antibiotics 3, 4.
This highlights the immediate call for upgraded antibacterial agents with an advanced mechanism for clinical application 5, 6.
Potential Target Sites for the Search of Futuristic Antimicrobials: The treatment of infectious diseases becomes knotty as microbial resistance shoots up at odds with antimicrobial agents. Drugs that destroy microbes prevent their proliferation and pathogenic actions have dissimilar structures, inconsistent affinity towards target site, and disparate spectrum of activity with various mechanism of action. The advancement in bacterial genomics has greatly altered the antimicrobial therapeutic environment, and many potential targets stand by 7, 8.
Attempts have been made for the revelation of unhackneyed antimicrobial agents, and many researchers have taken initiative steps intended to disclose ultra-modern drugs acting via advanced mechanisms or against the latest target sites from natural sources 9. The probable targets for the search for new antimicrobial compounds may be focused on the following mechanisms 8 are depicted in Fig. 1 as follows.
FIG. 1: POTENTIAL TARGET SITES FOR ANTIMICROBIAL AGENTS
Inhibition of Microbial Cell wall Synthesis: Bacterial cells are surrounded by a cell wall made of peptidoglycan network constitutes an essential component of the cell wall, serves as a perfect site for drug design since corresponding biosynthetic process are lacking in mammalian hosts. Blockage of bacterial cell wall synthesis is of paramount importance for the action of antimicrobials. The probable target sites 10-13, 8 in cell wall synthesis are summarized in Fig. 2 may be.
FIG. 2: TARGET SITES IN CELL WALL SYNTHESIS
Alanine racemase Promising Target for Antimicrobial agents: Alanine racemase (Alr, EC 5.1.1.1) is a pyridoxal-5- phosphate (PLP) dependent homodimeric enzyme that bring about reversible racemization of L- alanine and D- alanine. This bacterial enzyme execute predominating role in cell wall synthesis of bacteria 14, 15 by providing D- alanine (D-ala) which serve as a key molecule for the biosynthesis of peptidoglycan network of mycobacterial cell wall; hence its inhibition has been reported to be fatal to pathogen viability in the deprivation of D-alanine supplementation 16, 17. The lipid-rich mycobacterial cell wall is common amidst prokaryotes, making Alanine racemase a putative target for the design and development of pharmacologically active drugs 18-21. D-alanine provided by Alanine racemase is utterly vital for maintaining the growth and integrity of the cell wall. D-alanine acts as a pivotal precursor for peptidoglycan biosynthesis in bacterial cell walls via D-ala-D-ala formed by enzyme D-ala-D-ala ligase 22. This manifests how the inhibition of alanine racemase is important. In this paper, an overview on the updated status of reported Alanine racemase inhibitors has been provided based on shreds of literature. The products derived from natural sources have been recognized to play a significant role by being the lead molecules to be selected as potential candidates for drug development. Various researchers have synthesized derivatives of different scaffolds and evaluated them for Alanine racemase properties, summarized in Table 1.
TABLE 1: REPORTED INHIBITORS OF ENZYME ALANINE RACEMASE
In drug discovery, computer-aided drug design (CADD) offers effective and reliable methodologies for lead optimization, virtual screening and designing of new drug candidates. Molecular docking is a computational drug design approach used for providing insights into molecular recognition 41. In an attempt to conduct wet laboratory experiments smoothly and effectively, this method is useful for predicting the compound architecture, preferred orientation and con-formation (binding pose), interaction, and binding geometry of small ligands into the catalytic pockets of the biomolecular target based on docking score function 42. Based on literature evidence, molecular docking studies of some reported Alanine racemase Inhibitors have been presented in Table 2.
TABLE 2: REPORTED MOLECULAR DOCKING-BASED STUDIES OF ALANINE RACEMASE INHIBITORS
CONCLUSION: The imperative role of alanine racemase in mycobacterium cell wall synthesis implies that its inhibition is of utmost priority in dealing with various pathogenic infections. This paper provides an overview of structural information on variously reported inhibitors of alanine racemase based on convincing shreds of evidence from literature so that more precise inhibitors could be explored, designed and identified to rationalize the overall drug discovery process, which will be true serendipity for the mankind.
ACKNOWLEDGEMENT: We would like to acknowledge and express our obligations to our Dean, Faculty of Pharmaceutical Sciences, Baba Mastnath University, Asthal Bohar, Rohtak and Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, for providing necessary help.
CONFLICTS OF INTEREST: The authors declare no conflict of interest, financial or otherwise.
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How to cite this article:
Rathee P, Saini S and Khatkar A: An updated status of alanine racemase inhibitors: a review. Int J Pharm Sci & Res 2023; 14(2): 696-03. doi: 10.13040/IJPSR.0975-8232.14(2).696-03.
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IJPSR
P. Rathee, S. Saini and A. Khatkar *
Faculty of Pharmaceutical Sciences, B. M. University, Rohtak, Haryana, India.
anuragpharmacy@gmail.com
30 October 2022
27 November 2022
30 November 2022
10.13040/IJPSR.0975-8232.14(2).696-03
01 February 2023