RESUMO
The growing concerns and cases of COVID-19 with the appearance of novel variants i.e., BA.2.75. BA.5 and XBB have prompted demand for more effective treatment options that could overcome the risk of immune evasion. For this purpose, discovering novel small molecules to inhibit druggable proteins such as PLpro required for viral pathogenesis, replication, survival, and spread is the best choice. Compounds from the Dark chemical matter (DCM) database is consistently active in various screening tests and offer intriguing possibilities for finding drugs that are extremely selective or active against uncommon targets. Considering the essential role of PLpro, the current study uses DCMdatabase for the identification of potential hits using in silico virtual molecular screening and simulation approaches to inhibit the current and emerging variants of SARS-CoV-2. Our results revealed the 10 best compounds with docking scores between -7.99 to -7.03 kcal/mol better than the control drug (GRL0617) among which DC 5977-0726, DC 6623-2024, DC C879-0379 and DC D135-0154 were observed as the best hits. Structural-dynamics properties such as dynamic stability, protein packing, and residue flexibility demonstrated the pharmacologically favorable properties of these top hits in contrast to GRL0617. The hydrogen bonding half-life revealed that Asp164, Arg166, Tyr264, and Tyr268 have major contributions to the hydrogen bonding during the simulation. However, some of the important hydrogen bonds were missing in the control drug (GRL0617). Finally, the total binding free energy was reported to be -34.41 kcal/mol for GRL0617 (control), -41.03 kcal/mol for the DC5977-0726-PLpro, for the DC6623-2024-Plpro complex the TBE was -48.87 kcal/mol, for the for DCC879-0379-Plpro complex the TBE was -45.66 kcal/mol while for the DCD135-0154-PLpro complex the TBE was calculated to be -40.09 kcal/mol respectively, which shows the stronger potency of these compounds against PLpro and further in in vivo and in vitro test are required for the possible usage as potential drug against SARS-CoV-2.
RESUMO
A.D. is a common disease among other neurodegenerative disorders primarily developing due to amyloid-ß (Aß) neurotoxicity derived from the amyloid-ß protein precursor (AßPP). The amyloid precursor-like proteins 1 and 2 (APP1 and APLP2) biochemically behave similarly in many aspects to AßPP. 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 Aß 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.
