Comparative binding analysis of WGX50 and Alpha-M with APP family proteins APLP1 and APLP2 using structural-dynamics and free energy calculation approaches

Abstract

A.D. is a common disease among other neurodegenerative disorders primarily developing due to amyloid-β (Aβ) neurotoxicity derived from the amyloid-β protein precursor (AβPP). The amyloid precursor-like proteins 1 and 2 (APP1 and APLP2) biochemically behave similarly in many aspects to AβPP. We, therefore, proposed to test WGX-50 and Alpha-M for their interaction mechanism with APLP1 and APLP2 because both these drug candidate compounds previously showed inhibition of Aβ aggregation. We employed a comparative atomic investigation on Alpha-M and WGX-50 in complex with novel targets, i.e., APLP1 and APLP2, using biophysical and molecular simulation methods. The docking score was −6.83 kcal mol⁻¹ for Alpha-M–APLP1, −8.41 kcal mol⁻¹ for WGX-50–APLP1, −7.02 kcal mol⁻¹ for Alpha-M–APLP2 and −8.25 kcal mol⁻¹ for the WGX-50–APLP2 complex. Our results also elaborate that in the case of their interaction with both APLP1 and APLP2, the WGX-50 complex exhibits better stability than the APLP1/2-Alpha-M complexes during simulation. Furthermore, WGX50 in both APLP1 and APLP2 stabilized the internal flexibility upon binding in contrast to the Alpha-M complexes. The data showed that the BFE for Alpha-M–APLP1 was calculated to be −27.38 ± 0.93 kcal mol⁻¹, for WGX-50–APLP1 −39.65 ± 0.95 kcal mol⁻¹, for Alpha-M–APLP2 −24.80 ± 0.63 kcal mol⁻¹ while for WGX-50–APLP2 the BFE was −57.16 ± 1.03 kcal mol⁻¹ respectively. These results highlight that APLP2-WGX50 has greater binding energies in all four systems. PCA and FEL analysis further revealed variations in the dynamic behavior of these complexes. Overall, our findings demonstrate that WGX50 potentially acts as a more potent inhibitor for APLP1 and APLP2 than Alpha-M and thus shows the diverse pharmacological potential of WGX50. Due to its stable binding interaction, WGX50 might be a suitable candidate drug compound for targeting these precursors under pathological conditions.