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In 2020, cancer-related deaths reached 9.96 million globally, of which China accounted for 3 million, ranking first in the world. Phosphoglycerate mutase 1 (PGAM1) is a key metabolic enzyme in glycolysis, catalysing the conversion of 3-phosphoglycerate to 2-phosphoglycerate. Based on the excellent anticancer activity of PGMI-004A and HKB99, new small molecules with an anthraquinone core were synthesised to inhibit tumour growth. Developing small molecules with an anthraquinone core targeting PGAM1 may be an effective strategy for treating cancer. In this study, accelerated molecular dynamics (aMD) simulation, dynamic cross-correlation map (DCCM) calculation, principal component analysis (PCA) and free energy landscape (FEL) analysis were used to analyse conformational changes of PGAM1 caused by binding of inhibitors 8KX, 9HU and HKB. DCCM calculations and PCA showed that inhibitor binding significantly affected the kinetic behaviour of PGAM1 and conformational rearrangement of PGAM1. The binding ability and mechanism of 8KX, 9HU and HKB to PGAM1 were studied using the molecular mechanics generalised Born surface area (MM-GBSA) method. The results showed that compared with 8KX, the binding ability of 9HU and HKB to PGAM1 was enhanced by sulphonamide reversal and aminocarboxyl trifluoromethyl substitution. There were several hydrophobic interactions between inhibitors and PGAM1, providing significant contributions for inhibitor binding. Calculation of residue-based free energy decomposition revealed that F22, R90, Y92, L95, V112, W115, R116, V121, P123, P124, R191 and M206 were key residues of the PGAM1–inhibitor interaction and could be used as effective targets for designing drugs that inhibit the activity of PGAM1. [ABSTRACT FROM AUTHOR]

Conventional methods for measuring viscosity rely on macroscopic device components, which are difficult to miniaturize. The magnetic nano‐stirbars are small enough to enter tiny spaces and can spin without precise installation, making them an ideal candidate for exploring new methods. It is shown that a dense layer of Au nanowires can be grown on the silica surface of the nano‐stirbars, as a means to modulate the viscous resistance during their spinning and to make them visible under an optical microscope. The uniform growth of Au nanowires and the slight fluctuation of the spinning rates are investigated. It is shown that the nano‐stirbars with the hairy layer of Au nanowires can be used to measure the viscosity in microscopic liquid systems, such as microfluidic chambers and capillary tubes, involving cell media and blood samples. It is believed that the success with the proof‐of‐concept tests will open a window for further miniaturization of the nano‐stirbars for measuring in ultrasmall systems. [ABSTRACT FROM AUTHOR]

Bromodomain-containing protein 4 (BRD4) is critical in cell cycle regulation and has emerged as a potential target for treatment of various cancers. BRD4 contains two bromodomains, namely BDl and BD2. Research suggests that selectively inhibiting BDl or BD2 may provide more effective treatment options. Therefore, understanding the selective mechanism of inhibitor binding to BDl and BD2 is essential for development of high selective inhibitors to BDl and BD2. Multiple replica molecular dynamics (MRMD) simulations are utilized to investigate the binding selectivity of inhibitors SG3-179, GSK778, and GSK620 for BDl and BD2. The results show that BDl has stronger structural flexibility than BD2, moreover BDl and BD2 exhibit different internal dynamics. The analyses of free energy landscapes reveal significant differences in the conformational distribution of BDl and BD2. Binding free energy predictions suggest that entropy changes, electrostatic interactions, and van der Waals interactions are key factors in the selective binding of BDl and BD2 by SG3-179, GSK778, and GSK620. The calculations of the energy contributions of individual residues demonstrate that residues (W81, W374), (P82, P375), (Q85, K378), (V87, V380), (192, 1385), (N93, G386), (194, 1387), (C136, C429), (N140, N433), (K141, P434), (D144, H437) and (1146, V439) corresponding to (BDl, BD2) generate significant energy difference in binding of SG3-179, GSK778, and GSK620 to BDl and BD2, and they can serve as effective targets for development of high selective inhibitors against BDl or BD2. The related information may provide significant theoretical guidance for improving the selectivity of inhibitors for BDl and BD2. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to spread globally, and rapid viral evolution and the emergence of new variants pose challenges to pandemic control. During infection, the spike protein of SARS-CoV-2 interacts with the human ACE2 protein via its receptor binding domain (RBD), and it is known that engineered forms of ACE2 can compete with wild-type (WT) ACE2 for binding to inhibit infection. Here, we conducted multiple replica molecular dynamics (MRMD) simulations to study the mechanisms of the engineered ACE2 variants 3N39 and 3N94 and provide directions for optimization. Our findings reveal that engineered ACE2 is notably more efficacious in systems that show weaker binding to WT ACE2 (i.e., WT and BA.1 RBD), but also faces immune escape as the virus evolves. Moreover, by modifying residue types near the binding interface, engineered ACE2 alters the electrostatic potential distribution and reconfigures the hydrogen bonding network, which results in modified binding to the RBD. However, this structural rearrangement does not occur in all RBD variants. In addition, we identified potentially engineerable beneficial residues and potentially engineerable detrimental residues in both ACE2 and RBD. Functional conservation can thus enable the optimization of these residues and improve the binding competitiveness of engineered ACE2, which therefore provides additional immune escape prevention. Finally, we conclude that these findings have implications for understanding the mechanisms responsible for engineered ACE2 and can help us to develop engineered ACE2 proteins that show superior performance. [ABSTRACT FROM AUTHOR]