Leveraging shape screening and molecular dynamics simulations to optimize PARP1-Specific chemo/radio-potentiators for antitumor drug design

Hifza Khizer; Arooma Maryam; Adnan Ansari; Muhammad Sajjad Ahmad; Rana Rehan Khalid

doi:10.1016/j.abb.2024.110010

Leveraging shape screening and molecular dynamics simulations to optimize PARP1-Specific chemo/radio-potentiators for antitumor drug design

Arch Biochem Biophys. 2024 Apr 18:756:110010. doi: 10.1016/j.abb.2024.110010. Online ahead of print.

Authors

Hifza Khizer¹, Arooma Maryam², Adnan Ansari¹, Muhammad Sajjad Ahmad³, Rana Rehan Khalid⁴

Affiliations

¹ National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.
² Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
³ School of Chemical Engineering, Hebei University of Technology, Tianjin, 300401, PR China.
⁴ National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan. Electronic address: ray.binm@gmail.com.

PMID: 38642632
DOI: 10.1016/j.abb.2024.110010

Abstract

PARP1 plays a pivotal role in DNA repair within the base excision pathway, making it a promising therapeutic target for cancers involving BRCA mutations. Current study is focused on the discovery of PARP inhibitors with enhanced selectivity for PARP1. Concurrent inhibition of PARP1 with PARP2 and PARP3 affects cellular functions, potentially causing DNA damage accumulation and disrupting immune responses. In step 1, a virtual library of 593 million compounds has been screened using a shape-based screening approach to narrow down the promising scaffolds. In step 2, hierarchical docking approach embedded in Schrödinger suite was employed to select compounds with good dock score, drug-likeness and MMGBSA score. Analysis supplemented with decomposition energy, molecular dynamics (MD) simulations and hydrogen bond frequency analysis, pinpointed that active site residues; H862, G863, R878, M890, Y896 and F897 are crucial for specific binding of ZINC001258189808 and ZINC000092332196 with PARP1 as compared to PARP2 and PARP3. The binding of ZINC000656130962, ZINC000762230673, ZINC001332491123, and ZINC000579446675 also revealed interaction involving two additional active site residues of PARP1, namely N767 and E988. Weaker or no interaction was observed for these residues with PARP2 and PARP3. This approach advances our understanding of PARP-1 specific inhibitors and their mechanisms of action, facilitating the development of targeted therapeutics.

Keywords: BRCA mutations; Breast cancer; MMGB/PBSA calculations; Molecular dynamics simulation; Personalized medicine; Poly(ADP-Ribose) polymerase 1; Shape screening.