Identifying selective agonists targeting LXRß from terpene compounds of alismatis rhizoma.

Hyperlipidemia is thought of as an important contributor to coronary disease, diabetes, and fatty liver. Liver X receptor ß (LXRß) was considered as a validated target for hyperlipidemia therapy due to its role in regulating cholesterol homeostasis and immunity. However, many current drugs applied in clinics are not selectively targeting LXRß, and they can also activate LXRα which activates SREBP-1c that worked as an activator of lipogenic genes. Therefore, exploiting agonists selectively targeting LXRß is urgent. Here, computational tools were used to screen potential agonists selectively targeting LXRß from 112 terpenes of alismatis rhizoma. Firstly, a structural analysis between selective and nonselective agonists was used to explore key residues of selective binding with LXRß. Our data indicated that Phe271, Ser278, Met312, His435, and Trp457 were important to compounds binding with LXRß, suggesting that engaging ligand interaction with these residues may provide directions for the development of ligands with improved selective profiles. Then, ADMET analysis, molecular docking, MD simulations, and calculation of binding free energy and its decomposition were executed to screen the agonists whose bioactivity was favorable from 112 terpenes of alismatis rhizoma. We found that two triterpenes 16-hydroxy-alisol B 23-acetate and alisol M 23-acetate showed favorable ADMET properties and high binding affinity against LXRß. These compounds could be considered as promising selective agonists targeting LXRß. Our work provides an alternative strategy for screening agonists selectively targeting LXRß from alismatis rhizoma for hyperlipidemia disease treatment.

Screening of novel histone deacetylase 7 inhibitors through molecular docking followed by a combination of molecular dynamics simulations and ligand-based approach.

Histone acetylation/deacetylation is a key mechanism for transcription regulation which plays an important role in control of gene expression, tissue growth, and development. In particular, histone deacetylase 7 (HDAC7), a member of class IIa HDACs, is crucial to maintain cell homeostasis, and HDAC7 has emerged as a new target for cancer therapy. In this study, molecular docking was applied to screen candidate inhibitors and 21 compounds were found. Following the 50 ns molecular dynamics simulations and binding free energy calculation, ZINC00156160, ZINC01703144, ZINC04293665, and ZINC13900201 were identified as potential HDAC7 inhibitors, which would provide a sound starting point for further studies involving molecular modeling coupled with biochemical experiments. Meanwhile, similarity computation and substructure search were combined, and then we found that compounds sharing common backbone "CC(=O)N[C@@H](CSc1ccccc1)C(=O)O" could be efficient to inhibit the bioactivity of HDAC7. Then comparative molecular similarity indices analysis (CoMSIA) techniques were implemented to investigate the relationship between properties of the substituent group and bioactivities of small molecules. The CoMSIA model exhibited powerful predictivity, with satisfactory statistical parameters such as q2 of 0.659, R2 of 0.952, and F of 268.448. Contour maps of the CoMSIA model gave insight into the feature requirements of the common backbone for the HDAC7 inhibitory activity. Finally, details of designing novel HDAC7 inhibitors were confirmed by a combination of receptor-based docking and ligand-based structure-activity relationship. Communicated by Ramaswamy H. Sarma.

Structure and energy based quantitative missense variant effect analysis provides insights into drug resistance mechanisms of anaplastic lymphoma kinase mutations.

Anaplastic lymphoma kinase (ALK) is considered as a validated molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the effectiveness of molecularly targeted therapies using ALK inhibitors is almost universally limited by drug resistance. Drug resistance to molecularly targeted therapies has now become a major obstacle to effective cancer treatment and personalized medicine. It is of particular importance to provide an improved understanding on the mechanisms of resistance of ALK inhibitors, thus rational new therapeutic strategies can be developed to combat resistance. We used state-of-the-art computational approaches to systematically explore the mutational effects of ALK mutations on drug resistance properties. We found the activation of ALK was increased by substitution with destabilizing mutations, creating the capacity to confer drug resistance to inhibitors. In addition, results implied that evolutionary constraints might affect the drug resistance properties. Moreover, an extensive profile of drugs against ALK mutations was constructed to give better understanding of the mechanism of drug resistance based on structural transitions and energetic variation. Our work hopes to provide an up-to-date mechanistic framework for understanding the mechanisms of drug resistance induced by ALK mutations, thus tailor treatment decisions after the emergence of resistance in ALK-dependent diseases.

Structure and function analysis of Polygonatum cyrtonema lectin by site-directed mutagenesis.

The crystal structure of mature Polygonatum cyrtonema lectin (PCL) showed three similar carbohydrate-binding sites (CBS I, CBS II, and CBS III). The Gln58 and Asp60 residues of CBS II are substituted with His58 and Asn60. To establish the relationship between the key amino acid residues and structure or activity of PCL, we constructed four recombinant mutants in CBS I, CBS II, and CBS III. The experimental results indicate that CBS I, CBS III and the disulfide bond play vital roles in the binding with mannose. Furthermore, molecular dynamics simulations and binding free energy calculation illustrate that CBS I has a direct and strong relationship with the activity of PCL. CBS II does not play a critical role in the model for mannose binding by PCL. Although CBS III does not enhance the activity, it helps to maintain the activity and 3D structure. These results suggest that the carbohydrate-binding site of PCL may be in a hydrophilic environment, and Asn and Tyr are the key amino acids involved in its binding with sugar, but Gln and Asp are not necessary to maintain its activity.

In silico identification of potential inhibitors targeting Streptococcus mutans sortase A.

Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans (S. mutans) utilizes sortase A (SrtA) to anchor surface proteins to the cell wall and forms a biofilm to facilitate its adhesion to the tooth surface. Some plant natural products, especially several flavonoids, are effective inhibitors of SrtA. However, given the limited number of inhibitors and the development of drug resistance, the discovery of new inhibitors is urgent. Here, the high-throughput virtual screening approach was performed to identify new potential inhibitors of S. mutans SrtA. Two libraries were used for screening, and nine compounds that had the lowest scores were chosen for further molecular dynamics simulation, binding free energy analysis and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties analysis. The results revealed that several similar compounds composed of benzofuran, thiadiazole and pyrrole, which exhibited good affinities and appropriate pharmacokinetic parameters, were potential inhibitors to impede the catalysis of SrtA. In addition, the carbonyl of these compounds can have a key role in the inhibition mechanism. These findings can provide a new strategy for microbial infection disease therapy.

Insight into drug resistance mechanisms and discovery of potential inhibitors against wild-type and L1196M mutant ALK from FDA-approved drugs.

Anaplastic lymphoma kinase (ALK) plays a crucial role in multiple malignant cancers. It is known as a well-established target for the treatment of ALK-dependent cancers. Even though substantial efforts have been made to develop ALK inhibitors, only crizotinib, ceritinib, and alectinib had been approved by the U.S. Food and Drug Administration for patients with ALK-positive non-small cell lung cancer (NSCLC). The secondary mutations with drug-resistance bring up difficulties to develop effective drugs for ALK-positive cancers. To give a comprehensive understanding of molecular mechanism underlying inhibitor response to ALK tyrosine kinase mutations, we established an accurate assessment for the extensive profile of drug against ALK mutations by means of computational approaches. The molecular mechanics-generalized Born surface area (MM-GBSA) method based on molecular dynamics (MD) simulation was carried out to calculate relative binding free energies for receptor-drug systems. In addition, the structure-based virtual screening was utilized to screen effective inhibitors targeting wild-type ALK and the gatekeeper mutation L1196M from 3180 approved drugs. Finally, the mechanism of drug resistance was discussed, several novel potential wild-type and L1196M mutant ALK inhibitors were successfully identified.

Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer.

Breast cancer is one of the most lethal types of cancer in women worldwide due to the late stage detection and resistance to traditional chemotherapy. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Even though a substantial effort has been made to develop HER2 inhibitors, only lapatinib has been approved by the U.S. Food and Drug Administration (FDA). Side effects were observed in a majority of the patients within one year of treatment initiation. Here, we took advantage of bioinformatics tools to identify novel effective HER2 inhibitors. The structure-based virtual screening combined with ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction was explored. In total, 11,247 natural compounds were screened. The top hits were evaluated by an in vitro HER2 kinase inhibition assay. The cell proliferation inhibition effect of identified inhibitors was evaluated in HER2-overexpressing SKBR3 and BT474 cell lines. We found that ZINC15122021 showed favorable ADMET properties and attained high binding affinity against HER2. Moreover, ZINC15122021 showed high kinase inhibition activity against HER2 and presented outstanding cell proliferation inhibition activity against both SKBR3 and BT474 cell lines. Results reveal that ZINC15122021 can be a potential HER2 inhibitor.

Discover natural compounds as potential phosphodiesterase-4B inhibitors via computational approaches.

cAMP, intracellular cyclic adenosine monophosphate, is a ubiquitous second messenger that plays a key role in many physiological processes. PDE4B which can reduce the cAMP level by hydrolyzing cAMP to 5'-AMP has become a therapeutic target for the treatment of human diseases such as respiratory disorders, inflammation diseases, neurological and psychiatric disorders. However, the use of currently available PDE4B inhibitors is restricted due to serious side effects caused by targeting PDE4D. Hence, we are attempting to find out subfamily-selective PDE4B inhibitors from natural products, using computer-aided approaches such as virtual screening, docking, and molecular dynamics simulation. Finally, four potential PDE4B-selective inhibitors (ZINC67912770, ZINC67912780, ZINC72320169, and ZINC28882432) were found. Compared to the reference drug (roflumilast), they scored better during the virtual screening process. Binding free energy for them was -317.51, -239.44, -215.52, and -165.77 kJ/mol, better than -129.05 kJ/mol of roflumilast. The pharmacophore model of the four candidate inhibitors comprised six features, including one hydrogen bond donor, four hydrogen bond acceptors, and one aromatic ring feature. It is expected that our study will pave the way for the design of potent PDE4B-selective inhibitors of new drugs to treat a wide variety of diseases such as asthma, COPD, psoriasis, depression, etc.

An Overview of Predictors for Intrinsically Disordered Proteins over 2010-2014.

The sequence-structure-function paradigm of proteins has been changed by the occurrence of intrinsically disordered proteins (IDPs). Benefiting from the structural disorder, IDPs are of particular importance in biological processes like regulation and signaling. IDPs are associated with human diseases, including cancer, cardiovascular disease, neurodegenerative diseases, amyloidoses, and several other maladies. IDPs attract a high level of interest and a substantial effort has been made to develop experimental and computational methods. So far, more than 70 prediction tools have been developed since 1997, within which 17 predictors were created in the last five years. Here, we presented an overview of IDPs predictors developed during 2010-2014. We analyzed the algorithms used for IDPs prediction by these tools and we also discussed the basic concept of various prediction methods for IDPs. The comparison of prediction performance among these tools is discussed as well.