Structure-based discovery is often limited by rigid-receptor assumptions that miss induced fit. We present DRGSCROLL, a docking platform and webserver that jointly optimizes ligand pose and continuous receptor side-chain χ angles within an innovatıve genetic-algorithm (GA) search. The method initializes broad χ-angle populations, embeds steric-clash feasibility into dual-objective fitness, applies per-residue crossover and stochastic mutation to preserve physically realistic χ sets, and deliberately omits per-iteration minimization to allocate compute to expansive sampling; final poses are chosen by clash-free filtering and RMSD-based clustering. Across 50 PDBbind complexes, DRGSCROLL steadily reduced clash counts and improved docking energies over 50 GA generations (100 individuals/generation), indicating convergence to sterically viable, low-energy binding pockets that rigid protocols fail to access. Against established tools (i.e., Vina-GPU 2.1 and ADFR), DRGSCROLL sampled more favorable energy distributions and achieved lower medians, reflecting better induced-fit capture. In prospective virtual-screening style tests, DRGSCROLL improved actives-inactives discrimination for RET kinase and PARP1 while maintaining balanced precision-recall trade-offs. These results demonstrate that embedding continuous side-chain flexibility directly into the search (rather than post hoc rotamer tweaks or heavy local minimization) resolves key combinatorial and feasibility bottlenecks in flexible docking. DRGSCROLL provides a scalable, physics-grounded path to adaptive receptor-ligand modeling that enhances pose accuracy and early-enrichment for flexible targets and is broadly applicable from fragment screening to evaluation of synthetically ready or AI-generated small molecule libraries. To improve access, we provide a free webserver for academic and nonprofit users with a minimal interface—upload the protein and ligand PDB files and supply the Cartesian coordinates of the binding pocket. Platform page: drgscroll.com. Webserver: drgscroll.bau.edu.tr.
Sayyah et al. (Sun,) studied this question.
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