Coumarin-furo[2,3-]pyrimidone hybrid molecules targeting human liver cancer cells: synthesis, anticancer effect, EGFR inhibition and molecular docking studies.

The design, synthesis and investigation of antitumor activities of some coumarin-furo[2,3-]pyrimidone hybrid molecules are reported. , HepG2 cells were used to investigate the cytotoxicity of 6a-n and 10a-n. The results demonstrated that coupling a furopyrimidone scaffold with coumarin through a hydrazide linker can effectively improve their synergistic anticancer activity.

Role of Computer-Aided Drug Design in Drug Development.

The introduction of computational techniques to pharmaceutical chemistry and molecular biology in the 20th century has changed the way people develop drugs [...

Novel Coumarin-furo[2,3-d]pyrimidinone hybrid derivatives as anticancer agents: Synthesis, biological evaluation and molecular docking.

A series of coumarin-furo[2,3-d]pyrimidinone hybrid derivatives were synthesized, characterized by HR-MS, H NMR and C NMR. All synthesized compounds were evaluated for antiproliferative activities against hepatic carcinoma (HepG2) and cervical carcinoma (Hela) cell lines in vitro, and results shown that most of the compounds exhibited potent antitumor activity. Moreover, compound 3i, 8d and 8i were selected to induce apoptosis in HepG2 cells, and it displayed a significant concentration-dependent.

Comparison of the molecular mechanisms of Fuzi Lizhong Pill and Huangqin decoction in the treatment of the cold and heat syndromes of ulcerative colitis based on network pharmacology.

Objective: The aim of this study was to illuminate the similarities and differences of two prescriptions as "cold" and "heat" drugs for treating ulcerative colitis (UC) with the simultaneous occurrence of heat and cold syndrome via network pharmacology.

Methods: (1) Active compounds of Fuzi-Lizhong Pill (FLP) and Huangqin Decoction (HQT) were retrieved from the TCMSP database, and their common active compounds were compared using the Venn diagram. (2) Potential proteins targeted to three sets of compounds either (i) shared by FLP and HQT, (ii) unique to FLP or (iii) unique to HQT were screened from the STP, STITCH and TCMSP databases, and three corresponding core compound sets were identified in Herb-Compound-Target (H-C-T) networks.

In Silico Methods for Identification of Potential Active Sites of Therapeutic Targets.

Target identification is an important step in drug discovery, and computer-aided drug target identification methods are attracting more attention compared with traditional drug target identification methods, which are time-consuming and costly. Computer-aided drug target identification methods can greatly reduce the searching scope of experimental targets and associated costs by identifying the diseases-related targets and their binding sites and evaluating the druggability of the predicted active sites for clinical trials. In this review, we introduce the principles of computer-based active site identification methods, including the identification of binding sites and assessment of druggability.

Green synthesis, structure optimization and biological evalution of Rhopaladins' analog 2-styryl-5-oxopyrrolidine-2- carboxamide RPDPRH on CaSki cells.

We have synthesized Rhopaladins' analog (2,4)-4-chlorobenzylidene-2-(4-chlorostyryl)--cyclohexyl-1-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxamide (RPDPRH) via a highly facile, inexpensive and green approach and verified the structural superiority of compound RPDPRH through molecular docking. Moreover, we further detected the anti-proliferation, apoptosis and HPV E6/E7 effects of RPDPRH on CaSki cells. Finally, we confirmed that compared with the previous compound ()--(-butyl)-2-(4-chlorobenzoyl)-4-(4-fluorobenzylidene)-1-isopropyl-5-oxopyrrolidine-2-carboxamide (RPDPB), RPDPRH could better inhibit proliferation, induce apoptosis, and down-regulate HPV E6/E7 mRNA expression on Caski cells.

Discovery of 3-pyrazolyl-substituted pyrazolo[1,5-a]pyrimidine derivatives as potent TRK inhibitors to overcome clinically acquired resistance.

Several secondary tropomyosin receptor kinase (TRK) mutations located in the solvent front, xDFG, and gatekeeper regions, are a common cause of clinical resistance. Mutations in the xDFG motif in particular limit sensitivity to second-generation TRK inhibitors, which represent an unmet clinical need. We designed a series of 3-pyrazolyl-substituted pyrazolo[1,5-a]pyrimidine derivatives toward these secondary mutations using ring-opening and scaffold-hopping strategies.

In silico Methods for Identification of Potential Therapeutic Targets.

At the initial stage of drug discovery, identifying novel targets with maximal efficacy and minimal side effects can improve the success rate and portfolio value of drug discovery projects while simultaneously reducing cycle time and cost. However, harnessing the full potential of big data to narrow the range of plausible targets through existing computational methods remains a key issue in this field. This paper reviews two categories of in silico methods-comparative genomics and network-based methods-for finding potential therapeutic targets among cellular functions based on understanding their related biological processes.

Protocol for hit-to-lead optimization of compounds by auto ligand directing evolution (AILDE) approach.

Hit-to-lead (H2L) optimization is crucial for drug design, which has become an increasing concern in medicinal chemistry. A virtual screening strategy of auto ligand directing evolution (AILDE) has been developed to yield promising lead compounds rapidly and efficiently. The protocol includes instructions for fragment compound library construction, conformational sampling by molecular dynamics simulation, ligand modification by fragment growing, as well as the binding free energy prediction.

HISNAPI: a bioinformatic tool for dynamic hot spot analysis in nucleic acid-protein interface with a case study.

Protein-nucleic acid interactions play essential roles in many biological processes, such as transcription, replication and translation. In protein-nucleic acid interfaces, hotspot residues contribute the majority of binding affinity toward molecular recognition. Hotspot residues are commonly regarded as potential binding sites for compound molecules in drug design projects.

PIIMS Server: A Web Server for Mutation Hotspot Scanning at the Protein-Protein Interface.

Protein-protein interactions (PPIs) play vital roles in regulating biological processes, such as cellular and signaling pathways. Hotspots are certain residues located at protein-protein interfaces that contribute more in protein-protein binding than other residues. Research on the mutational effects of hotspots is important for understanding basic aspects of protein association.

Cloud 3D-QSAR: a web tool for the development of quantitative structure-activity relationship models in drug discovery.

Effective drug discovery contributes to the treatment of numerous diseases but is limited by high costs and long cycles. The Quantitative Structure-Activity Relationship (QSAR) method was introduced to evaluate the activity of a large number of compounds virtually, reducing the time and labor costs required for chemical synthesis and experimental determination. Hence, this method increases the efficiency of drug discovery.

Computational Approaches in Preclinical Studies on Drug Discovery and Development.

Because undesirable pharmacokinetics and toxicity are significant reasons for the failure of drug development in the costly late stage, it has been widely recognized that drug ADMET properties should be considered as early as possible to reduce failure rates in the clinical phase of drug discovery. Concurrently, drug recalls have become increasingly common in recent years, prompting pharmaceutical companies to increase attention toward the safety evaluation of preclinical drugs. and drug evaluation techniques are currently more mature in preclinical applications, but these technologies are costly.

Structure-activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy.

As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors.

Bioinformatics toolbox for exploring protein phosphorylation network.

A clear systematic delineation of the interactions between phosphorylation sites on substrates and their effector kinases plays a fundamental role in revealing cellular activities, understanding signaling modulation mechanisms and proposing novel hypotheses. The emergence of bioinformatics tools contributes to studying phosphorylation network. Some of them feature the visualization of network, enabling more effective trace of the underlying biological problems in a clear and succinct way.

Discovery of N-substituted-3-phenyl-1,6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2.

New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q.

Auto In Silico Ligand Directing Evolution to Facilitate the Rapid and Efficient Discovery of Drug Lead.

Motivated by the growing demand for reducing the chemical optimization burden of H2L, we developed auto in silico ligand directing evolution (AILDE, http://chemyang.ccnu.edu.

Discovery of Novel Pyrazole-Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.

ACID: a free tool for drug repurposing using consensus inverse docking strategy.

Drug repurposing offers a promising alternative to dramatically shorten the process of traditional de novo development of a drug. These efforts leverage the fact that a single molecule can act on multiple targets and could be beneficial to indications where the additional targets are relevant. Hence, extensive research efforts have been directed toward developing drug based computational approaches.

Crystal Structure of 4-Hydroxyphenylpyruvate Dioxygenase in Complex with Substrate Reveals a New Starting Point for Herbicide Discovery.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a promising target for drug and pesticide discovery. The unknown binding mode of substrate is still a big challenge for the understanding of enzymatic reaction mechanism and novel HPPD inhibitor design. Herein, we determined the first crystal structure of HPPD (HPPD) in complex with its natural substrate (HPPA) at a resolution of 2.

Separation and detection of cyproconazole enantiomers and its stereospecific recognition with chiral stationary phase by high-performance liquid chromatography.

Cyproconazole, a chiral triazole fungicide, has been diffusely used and analyzed. The development of an effective analytical method for cyproconazole enantiomers can support their residual monitoring and risk assessment. In the present study, the absolute configuration of the cyproconazole enantiomers was confirmed by electronic circular dichroism and time-dependent density functional theory.

Hydrophobicity-oriented drug design (HODD) of new human 4-hydroxyphenylpyruvate dioxygenase inhibitors.

Involved in the tyrosine degradation pathway, 4-hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for treating type I tyrosinemia. To discover novel HPPD inhibitors, we proposed a hydrophobicity-oriented drug design (HODD) strategy based on the interactions between HPPD and the commercial drug NTBC. Most of the new compounds showed improved activity, compound d23 being the most active candidate (IC = 0.

AIMMS suite: a web server dedicated for prediction of drug resistance on protein mutation.

Drug resistance is one of the most intractable issues for successful treatment in current clinical practice. Although many mutations contributing to drug resistance have been identified, the relationship between the mutations and the related pharmacological profile of drug candidates has yet to be fully elucidated, which is valuable both for the molecular dissection of drug resistance mechanisms and for suggestion of promising treatment strategies to counter resistant. Hence, effective prediction approach for estimating the sensitivity of mutations to agents is a new opportunity that counters drug resistance and creates a high interest in pharmaceutical research.