Objectives The large number of publications about Amaryllidaceae alkaloids reflects the abundance and variety in biological activity of these alkaloids. An in‐silico approach was implemented in this work to rationalize the individual alkaloids to molecular biological activity.

Methods A database was generated containing 313 Amaryllidaceae alkaloids which were then subjected to in‐silico‐validated structure‐based virtual screening using extra precision (XP) approach of Glide docking program. Further pharmacophore detection of the high scorers resulted in a hybrid model considering the structural and spatial characteristics of the molecules. The focus was laid on representative targets against viral infections, acetylcholinesterase and cancer. BEDROC studies were used for validation of the accuracy of docking methods.

Key findings As expected, galanthamine‐type alkaloids were the most active against hACHE; yet, lycorenine‐ and tazettine‐type alkaloids contributed significantly, while lycorine‐type alkaloids dominated the hit list against HIV‐1 PR target protein and were significantly active against HIV‐1 RT and influenza NA. Surprisingly, belladine‐type alkaloids showed the highest number of hits against HDAC2, while lycorine‐ and narciclasine‐type alkaloids dominated the hit lists against Aurora kinase A and VEGFR2.

Conclusions This report provides useful information on Amaryllidaceae alkaloids and serves as a starting point to access their undiscovered biological activity.

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