Complementing vaccine-induced and/or therapeutic anti-CSP Abs 41 , pre-erythrocytic circumsporozoite CSP could be targeted also by small drug-like molecules by traditional screening or by computational means. Difficulties are high for computational explorations of those possibilities, because of the CSP highly-disordered 3D repeats. Only the C-terminal domain has been crystallized, and no binding-drugs or docking cavities have been proposed. A preliminary exploration of some CSP possible docking cavities have been proposed here. By mimicking natural evolution as described above, computational predictions tailored initial ligands to CSP cavities to improve their affinities. Dozens of drug-like ligand conformers targeting either the ordered N-terminal SP and C-terminal α-helices or only the C-terminal cavities, were predicted with nanoMolar affinity ranges and low toxicities. Despite those predictions being highly hypothetical, drug-like high-affinity small molecules targeting the most conserved sequences of CSP could add new tools to circumsporozoite basic research.