Structure-based discovery of Licoflavone B and Ginkgetin targeting c-Myc G-quadruplex to suppress c-Myc transcription and myeloma growth.

G-quadruplex (G4), present in the c-Myc promoter, has emerged as an attractive cancer-specific molecular target for drug development. So, the discovery of small molecules to stabilize c-Myc-G4 to inhibit transcription of c-Myc protein is of great significance. Herein, a combined molecular docking-based virtual screening strategy, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation was conducted on the existing L6000 Natural Compound Library. Four natural compounds, including Licoflavone B, Demethyleneberberine, Ginkgetin, and Mulberroside C, were predicted to have preferable binding affinities to c-Myc G4 and then selected for commercial purchase and experimental evaluation. Compounds Licoflavone B and Ginkgetin can significantly inhibit myeloma cell proliferation, with IC50 values <8 µM against the RPMI-8226 cell line. Moreover, our data demonstrated that the two compounds could simultaneously downregulate c-Myc transcription and expression. Collectively, compounds Licoflavone B and Ginkgetin might be regarded as new candidates for the development of the more potent c-Myc-G4 stabilizers in the future.

Identification of Trovafloxacin, Ozanimod, and Ozenoxacin as Potent c-Myc G-Quadruplex Stabilizers to Suppress c-Myc Transcription and Myeloma Growth.

c-Myc is a major oncogene that is estimated to result in almost all human cancers and the c-Myc downregulation has become an attractive strategy for cancer treatment. For it is hard to design compounds that can directly interact with the c-Myc protein, the DNA G-quadruplex (G4) was discovered in its promoter region which was referred to as a potential drug target for controlling c-Myc expression. In this study, a combined strategy of molecular docking-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation was conducted on the existing FDA-Approved Drugs Library, eight compounds were selected for further experimental assay. Among them, five compounds exhibited dose-dependently anticancer activities against RPMI-8226 cells with IC50 values less than 18.4 µM. Further experiments showed that Trovafloxacin, Ozanimod, and Ozenoxacin decreased c-Myc mRNA level obviously and downregulated c-Myc expression significantly. In summary, compounds Trovafloxacin, Ozanimod, and Ozenoxacin might be regarded as new c-Myc G4 stabilizers for the treatment of c-Myc related cancers in the future.

Comparative analysis of compound NSC13728 as Omomyc homodimer stabilizer by molecular dynamics simulation and MM/GBSA free energy calculation.

Myc is a master transcriptional regulator that controls almost all cellular processes, whose function is dependent on dimerization with its obligate partner Max. Stabilization of Max homodimer by small molecules (such as compound NSC13728) has proven an effective way to reduce the availability of Myc-Max dimer. Omomyc, a peptide inhibitor of Myc, is able to form Omomyc homodimer, which can competitively inhibit the binding of Myc-Max to the E-box of DNA. Considering the high amino acid sequence homology between Omomyc and Max, we put forward the hypothesis that Max-Max stabilizers could stabilize the Omomyc homodimer. Hence, through molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation, we discovered that the stability of Omomyc-Omomyc is remarkably higher than that of Max-Max. Moreover, after adding the compound NSC13728 into the well-defined "Site 3," the binding affinity between two Omomyc monomers can be further increased. Compound NSC13728 has stronger binding interaction to Omomyc-Omomyc than to Max-Max. "Site 3" of Omomyc is more hydrophobic than that of Max, which enlightens us that the more potent Omomyc-Omomyc stabilizers may be hydrophobic in structure.

Computational Insights Into the Effects of the R190K and N121Q Mutations on the SARS-CoV-2 Spike Complex With Biliverdin.

The SARS-CoV-2 spike has been regarded as the main target of antibody design against COVID-19. Two single-site mutations, R190K and N121Q, were deemed to weaken the binding affinity of biliverdin although the underlying molecular mechanism is still unknown. Meanwhile, the effect of the two mutations on the conformational changes of "lip" and "gate" loops was also elusive. Thus, molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation were conducted on the wild-type and two other SARS-CoV-2 spike mutants. Our simulations indicated that the R190K mutation causes Lys190 to form six hydrogen bonds, guided by Asn99 and Ile101, which brings Lys190 closer to Arg102 and Asn121, thereby weakening the interaction energy between biliverdin and Ile101 as well as Lys190. For the N121Q mutation, Gln121 still maintained a hydrogen bond with biliverdin; nevertheless, the overall binding mode deviated significantly under the reversal of the side chain of Phe175. Moreover, the two mutants would stabilize the lip loop, which would restrain the meaningful upward movement of the lip. In addition, N121Q significantly promoted the gate loop deviating to the biliverdin binding site and compressed the site. This work would be useful in understanding the dynamics binding biliverdin to the SARS-CoV-2 spike.

Design, Synthesis and Pharmacological Evaluation of Naphthofuran Derivatives as Potent SIRT1 Activators.

Diabetic nephropathy (DN) is one of the most important medical complications in diabetic patients, which is an essential cause of end-stage renal disease in diabetic patients and still lacks effective medicines. Silent information regulator 1 (SIRT1) is closely related to the occurrence and development of DN. Activation of SIRT1 could significantly improve the symptoms of DN, while the activities of SIRT1 activators need to be further improved. Based on the crystal structure of SIRT1, structure and ligand-based approaches were carried out, and a lead compound 4,456-0661 (renamed as M1) was identified. Moreover, seven M1 analogues (6a-6g) were designed using a structure-based drug design strategy followed by bioactivity evaluation with SRTR2104 used as positive drugs. Among the target molecules, compounds M1, 6b, and 6d were proved to be potent SIRT1 activators, the activities of which are comparable to SRT2104. More importantly, compounds M1, 6b, and 6d could resist high glucose-induced apoptosis of HK-2 cells by activating SIRT1 and deacetylation of p53. Apart from the beneficial effect on apoptosis of DN, these compounds also alleviated high glucose stimulating inflammation response in HK-2 cells through SIRT1/NF-κB (p65) pathway. Consequently, M1, 6b, and 6d could be promising drug candidates for SIRT1 related diseases.

Nanoscale Structural Modulation and Low-temperature Magnetic Response in Mixed-layer Aurivillius-type Oxides.

Nanoscale structural modulation with different layer numbers in layer-structured complex oxides of the binary Bi4Ti3O12-BiFeO3 system can give rise to intriguing phenomena and extraordinary properties, originating from the correlated interfaces of two different phases with different strain states. In this work, we studied the nanoscale structural modulation induced by Co-substitution in the Aurivillius-type oxide of Bi11Fe3Ti6O33 with a unique and naturally occurred mixed-layer structure. Nanoscale structural evolution via doping occurred from the phase-modulated structure composed of 4- and 5-layer phases to a homogeneous 4-layer structure was clearly observed utilizing x-ray diffraction and electron micro-techniques. Significantly, magnetic response for the samples under various temperatures was recorded and larger magnetic coercive fields (e.g. H c ∼ 10 kOe at 50 K) were found in the phase-modulated samples. Analyses of the x-ray absorption spectra and magnetic response confirmed that the low-temperature magnetic behaviour should be intrinsic to the phase-modulated structure inside the structural transformation region, mainly arising from structural distortions at the correlated interfaces.