IN SILICO IDENTIFICATION OF DCTPP1 LIGANDS THROUGH PHARMACOPHORE-BASED VIRTUAL SCREENING WITH ADMET EVALUATION, MOLECULAR DOCKING, AND MOLECULAR DYNAMICS

Deoxycytidine triphosphate pyrophosphatase 1 (DCTPP1) hydrolyzes non-canonical deoxynucleoside triphosphates, preventing their incorporation into DNA. Its overexpression has been associated with tumor progression and chemoresistance, making DCTPP1 a promising target for inhibitor development. This study aimed to identify novel compounds that target DCTPP1 using pharmacophore-based virtual screening, followed by ADMET evaluation, molecular docking, and molecular dynamics simulations. The crystal structure of DCTPP1 (PDB ID: 7MU5) was analyzed with CavityPlus and FTMap to identify druggable pockets. A main cavity pharmacophore model was used in Pharmit to screen PubChem entries with molecular weight <500 g mol−1. Reducing pharmacophore constraints increased chemical diversity, finding 36 candidate ligands. Docking with GNINA revealed three main molecules: MOL1 (−9.13 kcal mol−1), MOL2 (−8.70 kcal mol−1), and MOL3 (−8.56 kcal mol−1). The crystallographic ligand triptolide was redocked for comparison, resulting in −7.13 kcal/mol and an RMSD of 0.33 Å relative to the experimental pose. ADMET predictions indicated that all compounds satisfied the common drug-likeness criteria. MOL1 and MOL3 exhibited high plasma protein binding, while MOL2 showed lower protein binding but a predicted genotoxicity alert that requires experimental follow-up. All systems were simulated in 100 ns MD and maintained RMSD ≈ 0.18 0.25 nm. The DCTPP1-MOL2 complex exhibited marginally lower RMSD and sharper RDF peaks, consistent with persistent contacts and stabilization of the native conformation. In contrast, MOL3 exhibited higher RMSD, broader RDF peaks, and a fragmented free energy landscape, indicating greater conformational heterogeneity and less specific interactions. RMSF analysis indicated increased mobility at the N terminus, in a central loop near residues 70–80, and at the C-terminus; MOL2 reduced and MOL3 increased these fluctuations. PCA and free energy mapping demonstrated that MOL2 overlaps with the apo conformational space, MOL1 is intermediate, and triptolide stabilizes a distinct alternative conformation. In conclusion, MOL2 emerges as the prime candidate for experimental validation and chemical optimization as a DCTPP1 ligand, combining persistent interactions, conformational stability, and preservation of native dynamics.