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Bioinformatic Analysis of the Nicotinamide Binding Site in Poly(ADP-Ribose) Polymerase Family Proteins

Garri Manasaryan1, Dmitry Suplatov2, Sergey Pushkarev3

  • 1Faculty of Medicine, Lomonosov Moscow State University, Lomonosov Ave. 27, bldg. 1, 119991 Moscow, Russia.

Cancers
|April 3, 2021
PubMed

Insights

This study identifies key mutations and D-loop mobility in the nicotinamide (NA) binding site of Poly (ADP-ribose) polymerase (PARP) enzymes. These factors can guide the development of selective PARP inhibitors for cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Bioinformatics

Background:

  • The Poly (ADP-ribose) polymerase (PARP) family has 17 members involved in critical cellular functions, including cancer cell viability.
  • Current PARP inhibitors show limited selectivity across family members, leading to significant adverse effects.
  • The nicotinamide (NA) binding site is a crucial functional region within PARP enzymes.

Purpose of the Study:

  • To conduct a family-wide investigation of the NA binding site in PARP enzymes.
  • To identify structural factors that can enhance the selectivity of PARP inhibitors.
  • To inform the development of novel anticancer therapeutics targeting specific PARP family members.

Main Methods:

  • Comparative bioinformatic analysis of the PARP family.
  • Molecular modeling of the NA binding site and surrounding regions.
  • Identification of mutations and analysis of D-loop mobility.

Main Results:

  • Specific mutations within the NA binding site were identified as potential determinants of inhibitor selectivity.
  • The mobility of the D-loop region adjacent to the NA site was found to influence binding.
  • These findings provide a basis for designing more targeted PARP inhibitors.

Conclusions:

  • Mutations and D-loop dynamics in the NA binding site are critical for developing selective PARP inhibitors.
  • This research is particularly relevant for creating new tankyrase (PARPs 5a and 5b) inhibitors for cancer treatment.
  • The study offers a rational approach to minimize off-target effects and improve therapeutic efficacy.
Keywords:
7-methylguanineD-loophomology modelinginhibitormolecular dynamicsnicotinamidepoly(ADP-ribose) polymerasetankyrase

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