ABSTRACT HIV‐1 protease is a key therapeutic target for antiretroviral drug development. In this study, a structure‐based high‐throughput virtual screening (HTVS) approach was employed to identify novel quinazoline‐based inhibitors targeting the protease's catalytic site. A library of 5000 compounds from the PubChem database was screened, and CID‐2135609 emerged as the top hit with the strongest binding affinity (–12.39 kcal/mol). In addition to its superior docking score, CID‐2135609 exhibited favorable drug‐like properties, including optimal molecular weight, high Caco‐2 permeability, balanced lipophilicity, and acceptable blood‐brain barrier penetration. Molecular docking revealed that CID‐2135609 engages key catalytic residues (Asp25, Ile50, Gly49) through van der Waals and π‐interactions, with additional contributions from Arg8, Asp30, and Ile47. Thermodynamic profiling indicated that binding is exothermic and entropically favorable, driven by hydrophobic contacts and water displacement, with a negative ΔG confirming spontaneous association. All‐atom molecular dynamics simulations over 200 ns demonstrated that CID‐2135609 maintains stable binding within the active site, preserving critical contacts while adapting its orientation to enhance fit. The protease structure remained conformationally stable, with minimal deviation in secondary structure or global compactness. Time‐resolved interaction profiling revealed sustained and expanded interactions with residues including Pro81, Ile84, and Thr80. Comparative analysis with the apo form showed reduced solvent exposure and conformational flexibility upon ligand binding, as supported by SASA and PCA analyses. Free energy decomposition further validated complex stability. Overall, CID‐2135609 is a promising candidate for HIV‐1 protease inhibition and merits further experimental validation.
Ahmad et al. (Fri,) studied this question.