The most commonly accepted hypothesis of Alzheimer's disease (AD) is the amyloid hypothesis caused due to formation of accumulation of Aβ42 isoform, which leads to neurodegeneration. In this regard, presenilin-1 (PSEN-1) and -2 (PSEN-2) proteins play a crucial role by altering the amyloid precursor protein (APP) metabolism, affecting γ-secretase protease secretion, finally leading to the increased levels of Aβ. In the absence of reported commercial pharmacotherapeutic agents targeting presenilins, we aim to propose benzophenone integrated derivatives (BIDs) as the potential inhibitors of presenilin proteins through in silico approach. The study evaluates the interaction of BIDs through molecular docking simulations, molecular dynamics simulations, and binding free energy calculations. This is the first ever computational approach to discover the potential inhibitors of presenilin proteins. It also comprises druglikeliness and pharmacotherapeutic potential analysis of the compounds. Out of all the screened BIDs, BID-16 was found to be the lead compound against both the presenilin proteins. Based on these results, one can evaluate BID-16 as an anti-Alzheimer's potential specifically targeting presenilin proteins in near future using in vitro and in vivo methods.