Quantum Chemical Tailoring of Donor–Acceptor Organic Nanomedicines for Nonlinear Optical Performance and Theragnostic Applications: Molecular Descriptors, In Silico, and Ab Initio Investigations

Nonlinear optical (NLO) active chromophores and their applications in photothermal therapy (PTT) demonstrate great potential in modern theragnostics, owing to their efficient light–matter interactions. A recognized D–π–A chromophore, FTC-3f, which is reported to exhibit a high photothermal conversion efficiency (~51.11%), was structurally modified with various spacers and acceptors to elucidate enhanced PTT and NLO behavior through DFT and TD-DFT simulations. Molecular geometries were optimized at the B3LYP/6-31G (d, p) level. Their electronic properties, charge separation, and efficient transition pathways were analyzed using frontier molecular orbitals (FMOs), density of states (DOS), UV–visible spectroscopy, photon-induced electron transfer (PET), and transition density matrix (TDM) analysis. Among all the derivatives, D4 exhibited the smallest HOMO–LUMO energy gap (1.701 eV). The highest first-order hyperpolarizability (β) values are found for D4 (1.50 × 105 in the gas phase, 7.40 × 105 in water, 3.06 × 105 in benzene solvent). The βHRS is found to be in the range 5.11 × 104 to 2.97 × 104 and DR (3.65 × 105 to 4.53 × 104) supports the strong NLO response and strong synergistic donor–acceptor interactions. The designed chromophores exhibit much higher SHG and EOPE responses at 532, 1907.21, and 1064 nm than FTC-3F, indicating great potential for the synthesis of effective NLO nanomedicine. Molecular docking with bovine serum albumin (PDB ID: 4F5S) and Bcl-2 (PDB ID: 2W3L) suggested favorable binding conformations, consistent with a potential for transport and apoptotic-targeting behavior. All 3D molecular descriptor parameters indicate that the designed chromophores have potential for preferential targeting in PTT. This study investigates how structural modifications of donor–π–acceptor chromophores influence their electronic, optical, nonlinear optical, and theragnostic properties, providing insights into molecular design strategies for advanced NLO-based nanomedicine applications.