Identification of PARP12 Inhibitors By Virtual Screening and Molecular Dynamics Simulations

Tahani M Almeleebia; Shahzaib Ahamad; Irfan Ahmad; Ahmad Alshehri; Ali G Alkhathami; Mohammad Y Alshahrani; Mohammed A Asiri; Amir Saeed; Jamshaid Ahmad Siddiqui; Dharmendra K Yadav; Mohd Saeed

doi:10.3389/fphar.2022.847499

Identification of PARP12 Inhibitors By Virtual Screening and Molecular Dynamics Simulations

Front Pharmacol. 2022 Aug 9:13:847499. doi: 10.3389/fphar.2022.847499. eCollection 2022.

Authors

Affiliations

¹ Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia.
² School of Biotechnology, IFTM University, Moradabad, India.
³ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
⁴ College of Applied Medical Sciences, Najran University, Najran, Saudi Arabia.
⁵ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia.
⁶ Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Medical Sciences and Technology, Khartoum, Sudan.
⁷ Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India.
⁸ Department of Pharmacy, Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University of Medicine and Science, Incheon, South Korea.
⁹ Department of Biology, College of Sciences, University of Hail, Hail, Saudi Arabia.

Abstract

Poly [adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that performs several fundamental cellular processes. Aberrant activity (mutation) in PARP12 has been linked to various diseases including inflammation, cardiovascular disease, and cancer. Herein, a large library of compounds (ZINC-FDA database) has been screened virtually to identify potential PARP12 inhibitor(s). The best compounds were selected on the basis of binding affinity scores and poses. Molecular dynamics (MD) simulation and binding free energy calculation (MMGBSA) were carried out to delineate the stability and dynamics of the resulting complexes. To this end, root means deviations, relative fluctuation, atomic gyration, compactness, covariance, residue-residue contact map, and free energy landscapes were studied. These studies have revealed that compounds ZINC03830332, ZINC03830554, and ZINC03831186 are promising agents against mutated PARP12.

Keywords: MD simulations; MMGBSA; PARP12; ZINC-FDA; virtual screening.