Design, synthesis, and structural elucidation of novel NmeNANAS inhibitors for the treatment of meningococcal infection


Autoři: Osama I. Alwassil aff001;  Sandeep Chandrashekharappa aff003;  Susanta K. Nayak aff004;  Katharigatta N. Venugopala aff001
Působiště autorů: Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Kingdom of Saudi Arabia aff001;  Department of Pharmaceutical Sciences, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia aff002;  Institute for Stem Cell Biology and Regenerative Medicine, NCBS, TIFR, GKVK, Bangalore, India aff003;  Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur, Maharashtra, India aff004;  Department of Biotechnology and Food Technology, Faculty of Applied Science, Durban University of Technology, Durban, South Africa aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223413

Souhrn

Neisseria meningitidis is the primary cause of bacterial meningitis in many parts of the world, with considerable mortality rates among neonates and adults. In Saudi Arabia, serious outbreaks of N. meningitidis affecting several hundreds of pilgrims attending Hajj in Makkah were recorded in the 2000–2001 season. Evidence shows increased rates of bacterial resistance to penicillin and other antimicrobial agents that are used in the treatment of the meningococcal disease. The host’s immune system becomes unable to recognize the polysialic acid capsule of the resistant N. meningitidis that mimics the mammalian cell surface. The biosynthetic pathways of sialic acid (i.e., N-acetylneuraminic acid [NANA]) in bacteria, however, are somewhat different from those in mammals. The largest obstacle facing previously identified inhibitors of NANA synthase (NANAS) in N. meningitidis is that these inhibitors feature undesired chemical and pharmacological characteristics. To better comprehend the binding mechanism underlying these inhibitors at the catalytic site of NANAS, we performed molecular modeling studies to uncover essential structural aspects for the ultimate recognition at the catalytic site required for optimal inhibitory activity. Applying two virtual screening candidate molecules and one designed molecule showed promising structural scaffolds. Here, we report ethyl 3-benzoyl-2,7-dimethyl indolizine-1-carboxylate (INLZ) as a novel molecule with high energetic fitness scores at the catalytic site of the NmeNANAS enzyme. INLZ represents a promising scaffold for NmeNANAS enzyme inhibitors, with new prospects for further structural development and activity optimization.

Klíčová slova:

Crystal structure – Enzyme inhibitors – Hydrogen bonding – Penicillin – Sialic acids – Zinc – Neisseria meningitidis – Meningococcal disease


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2019 Číslo 10