Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the GLA gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and central nervous system. In our previous study, we identified four GLA mutations from four independent Fabry disease families with kidney disease or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) and c.801+1G>A (p.L268fsX3). To reveal the molecular mechanism underlying the predisposition to Fabry disease caused by GLA mutations, we analyzed the effects of these four GLA mutations on the protein structure of α-galactosidase A using bioinformatics methods. The results showed that these mutations have a significant impact on the internal dynamics and structures of GLA, and all these altered amino acids are close to the enzyme activity center and lead to significantly reduced enzyme activity. Furthermore, these mutations led to the accumulation of autophagosomes and impairment of autophagy in the cells, which may in turn negatively regulate autophagy by slightly increasing the phosphorylation of mTOR. Moreover, the overexpression of these GLA mutants promoted the expression of lysosome-associated membrane protein 2 (LAMP2), resulting in an increased number of lysosomes. Our study reveals the pathogenesis of these four GLA mutations in FD and provides a scientific foundation for accurate diagnosis and precise medical intervention for FD.

Yersinia pestis, the causative agent of plague, is a Gram-negative bacterium. If the plague is not properly treated it can cause rapid death of the host. Bubonic, pneumonic, and septicemic are the three types of plague described. Bubonic plague can progress to septicemic plague, if not diagnosed and treated on time. The mortality rate of pneumonic and septicemic plague is quite high. The symptom-defining disease is the bubo, which is a painful lymph node swelling. Almost 50% of bubonic plague leads to sepsis and death if not treated immediately with antibiotics. The host immune response is slow as compared to other bacterial infections. Clinical isolates of Yersinia pestis revealed resistance to many antibiotics such as tetracycline, spectinomycin, kanamycin, streptomycin, minocycline, chloramphenicol, and sulfonamides. Drug discovery is a time-consuming process. It always takes ten to fifteen years to bring a single drug to the market. In this regard, in silico subtractive proteomics is an accurate, rapid, and cost-effective approach for the discovery of drug targets. An ideal drug target must be essential to the pathogen’s survival and must be absent in the host. Machine learning approaches are more accurate as compared to traditional virtual screening. In this study, k-nearest neighbor (kNN) and support vector machine (SVM) were used to predict the active hits against the beta-ketoacyl-ACP synthase III drug target predicted by the subtractive genomics approach. Among the 1012 compounds of the South African Natural Products database, 11 hits were predicted as active. Further, the active hits were docked against the active site of beta-ketoacyl-ACP synthase III. Out of the total 11 active hits, the 3 lowest docking score hits that showed strong interaction with the drug target were shortlisted along with the standard drug and were simulated for 100 ns. The MD simulation revealed that all the shortlisted compounds display stable behavior and the compounds formed stable complexes with the drug target. These compounds may have the potential to inhibit the beta-ketoacyl-ACP synthase III drug target and can help to combat Yersinia pestis-related infections. The dataset and the source codes are freely available on GitHub.

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.

Copper(II) complexes with a general formula [Cu₂(3,4-F₂C₆H₃CH₂COO)₄(L)₂], where L = 2-methylpyridine (1) and 3-methylpyridine (2), are reported here. The FTIR spectra of the complexes confirmed the bridging bidentate coordination mode of the carboxylate ligand. The low (475 and 449 cm⁻¹) and strong (727 & 725 cm⁻¹) intensity bands in the FTIR spectra, due to Cu-N stretches and pyridyl ring vibrations, confirmed coordination of the 2-/3-methyl pyridine co-ligands in complexes 1 and 2, respectively. A binuclear paddlewheel structural arrangement with a square pyramidal geometry was confirmed for copper atoms in the complexes via single-crystal X-ray analysis. The DPPH, ^•OH radical, and α-amylase enzyme inhibition assays showed higher activities for the complexes than for the free ligand acid. The binding constant (K_b = 1.32 × 10⁵ for 1 and 5.33 × 10⁵ for 2) calculated via UV-VIS absorption measurements and docking scores (−6.59 for 1 and −7.43 for 2) calculated via molecular docking showed higher SS-DNA binding potential for 2 compared to 1. Viscosity measurement also reflected higher DNA binding ability for 2 than 1. Both complexes 1 and 2 (docking scores of −7.43 and −6.95, respectively) were found to be more active inhibitors than the free ligand acid (docking score of −5.5159) against the target α-amylase protein. This in silico study has shown that the herein reported compounds follow the rules of drug-likeness and exhibit good potential for bioavailability.