The acetylcholinesterase enzyme (AChE) plays an important role in central and peripheral nervous systems. Acetylcholine (ACh) acts through the regulation of AChE activity, which can play a key role in accelerating senile amyloid β-peptide (Aβ) plaque deposition. Therefore, inhibition of the AChE enzyme can be used as a key principle to prevent ACh depletion. The present study has been emphasized to explore both ligand- and structure-based 3D QSAR, HQSAR, pharmacophore, molecular docking and simulation studies on a set of structurally diverse inhibitors to optimize prime structural features responsible for selective binding to AChE, and vis-à-vis inhibiting enzyme activity. The pharmacophore model showed the importance of HB acceptor and donor, positive ionization and hydrophobic features of the molecule for effective binding. Structure-based docking and simulation studies adjudged the significance of features obtained from ligand-based 3D QSAR, CoMFA (Q2 =.608, R2 pred =.700), CoMSIA (Q2 =.632, R2 pred =.734), HQSAR (Q2 =.850, R2 pred =.693) and pharmacophore (Q2 =.839, ROCscore =.769) models. The aim of the present study is to identify the essential structural and physicochemical profiles of molecules that can provide therapeutic benefits with less toxicity. Structurally diverse compounds have been used for the study, and the generated models showed the large applicability domain. © 2017 Informa UK Limited, trading as Taylor & Francis Group.