Computational Evaluation of Novel PARP-1 Inhibitors for Breast Cancer: Docking, Molecular Dynamics, MM/GBSA, DFT and ADMET Calculations

Abstract

Background/Objectives: Poly (ADP-ribose) polymerase (PARP1) has emerged as a promising therapeutic target in human breast cancer particularly in BRCA1/2 mutation carriers where a synthetic lethal interaction leads to massive tumor cell death upon specific inhibitors’ administration. Current clinically approved PARP inhibitors (Talazoparib and Olaparib) show outstanding therapeutic capabilities but suffer from severe side effects. Most importantly, some of them can cause life-threatening cardiotoxicity through hERG off-target effects. Here, we performed an extensive study to identify lead compounds with improved binding modes and favorable predicted pharmacokinetics using an integrated computational strategy. Methods: An artificial intelligence-driven drug design (AIDDISON™ v2023) workflow was employed to search ultra-large chemical space libraries for active compounds, which were then optimized via computer-aided methods to form a PARP-Tailored Database (PTD). This database was then analyzed through a virtual screening workflow, molecular docking studies, molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, DFT analysis and ADME/Tox predictions using the Schrödinger suite (v2023-2), MobaXterm v25.2, Gaussian 16.0, ProTox-3 and Pred-hERG v5.0 respectively. Results: Three compounds (1a–1c) were identified as promising candidates. Among them 1a appeared to be the most active compound with a favorable docking score (−9.488 kcal/mol) that is not only higher than 1b and 1c but also higher than that of Talazoparib (−6.778 kcal/mol). MD simulations of 1a–1c in the active site revealed an average RMSD of ~2.5–3.6 Å which is better compared to the parent Talazoparib (5.6 Å). Interestingly, on the 250 ns extended MD study, 1a exhibited a slightly reduced RMSD between 2.4 and 3.2 Å, whereas Talazoparib retained higher fluctuations of ~5 Å to 6 Å. MM/GBSA binding energy analysis indicated 1a to have better predicted binding affinity (−67.820 kcal/mol), which is also better than Talazoparib (−63.734 kcal/mol). DFT calculations showed good electronic properties and in silico ADMET studies also indicated 1a to have good drug-likeness and lower predicted hepatotoxicity and cardiotoxicity risk. Conclusions: These findings identify compound 1a as a promising lead, while compounds 1b and 1c remain viable candidates for further optimization. However, experimental validation is critical to confirm the predicted biological activity and safety profiles.