Comparative virtual screening of African natural products against sickle haemoglobin: the β-chain hydrophobic acceptor pocket outperforms the Valβ6 surface for lateral-contact inhibition

Sickle cell disease arises from the Gluβ6→Valβ6 substitution in haemoglobin, which drives polymerisation through a lateral contact where Valβ6 inserts into a hydrophobic acceptor pocket on an adjacent β-chain. We compared two non-covalent inhibition strategies – capping Valβ6 and plugging the acceptor pocket – by docking the 9 077-compound African Natural Products Database against both sites of the deoxy-HbS β-chain dimer. Pocket docking returned 1 238 hits below −7 kcal mol−¹ against 13 for the Valβ6 surface, a 137-fold difference in hit rate. Eleven 500 ns trajectories were then tested whether docking rank predicts function. The apo dimer separated within nanoseconds; the best Valβ6-capping compound remained bound yet failed to hold the chains together. Two porphyrin free-bases occupied the pocket and excluded Valβ6, but violate drug-likeness criteria. We therefore asked whether the mechanism requires a porphyrin. Garcinone E, a prenylated xanthone, was docked independently in MOE and Glide and simulated in triplicate: it occupied the pocket in 99.7 ± 0.4% of frames, recruited the same His63/His92 aromatic walls, and displaced Valβ6 more effectively than the porphyrin lead. Platform-blocking is a pharmacophore rather than a chemotype, which opens a tractable region of natural-product space.