[On the molecular drug design from viewpoint of precision medicine].

Precision medicine (PM) involves the application of "omics" analysis and system biology to analyze the cause of disease at the molecular level for targeted treatments of individual patient. Based on the targeted treatment PM is closely related to pharmaceuticals, which, as a therapeutic means and supply front, mainly embody the two aspects: drug discovery/development, and clinical administration. Innovation of new molecular entities with safety and specific efficacy is the prerequisite and guarantee for the PM practice; on the other hand, the outcome and clues in clinical PM feedback to new drug research.

[Concise analysis for innovation of pioneering and follow-on drugs].

More attention has been paid to the pioneering drug innovation since the new millennium, while the creation space of fast-followed drugs is shrinking due to the serious risks observed in the clinical phases following marketing. Innovative drug discovery aiming at the brand new target is dependent on the breakthrough in basic biology, followed by chemical biology, and medicinal chemistry. This roadmap requires harmonious environment and free exploration atmosphere, while mandatory planning unlikely accelerates drug discovery.

[Drug innovation and reverse thinking].

Drug innovation involves an individual molecular operation, and every new molecular entity features a hard-duplicated track of R&D. The transformation from an active compound to a new medicine carries out almost in a chaotic system devoid of regularity and periodic alteration. Since new millennium the dominant position in drug innovation has been occupied by the first-in-class drugs, yet the number of launched follow-on drugs has been distinctly decreased.

[Application of temperature sensitive yeast models with definite target in the screening of potential human Pin1 inhibitors].

This study is to explore new lead compounds by inhibition of Pin1 for anticancer therapy using temperature sensitive mutants. As Pin1 is conserved from yeast to human, we established a high-throughput screening method for Pin1 inhibitors, which employed yeast assay. This method led to the identification of one potent hits, 8-11.

[Ligand efficiency and lead optimization].

Pharmacological activity and druggability are two pivotal factors in drug innovation, which are respectively determined by the microscopic structure and macroscopic property of a molecule. Since structural optimization consists in a molecular operation in the space with multi-dimensions, and there exists a body of uncertainties for transduction from in vitro activity into in vivo pharmacological response. It is necessary for early stage in lead optimization to evaluate compound quality or efficiency using a kind of metrics containing multi-parameters.

[Challenges and strategies of drug innovation].

Drug research involves scientific discovery, technological inventions and product development. This multiple dimensional effort embodies both high risk and high reward and is considered one of the most complicated human activities. Prior to the initiation of a program, an in-depth analysis of "what to do" and "how to do it" must be conducted.

[Modification of natural products for drug discovery].

Pharmacological activity and druggability are two essential factors for drug innovation. The pharmacological activity is definitely indispensable, and the druggability is destined by physico-chemical, biochemical, pharmacokinetic and safety properties of drugs. As secondary metabolites of animals, plants, microbes and marine organisms, natural products play key roles in their physiological homeostasis, self-defense, and propagation.

[Drug promiscuity].

It is essential for a successful drug to possess two basic characteristics: satisfactory pharmacological action with sufficient potency and selectivity; good druggability with eligible physicochemical, pharmacokinetic and safety profiles, as well as structural novelty. Promiscuity is defined as the property of a drug to act with multiple molecular targets and exhibit distinct pharmacological effects. Promiscuous drugs are the basis of polypharmacology and the causes for side effects and unsuitable DMPK.

[Synthesis and activity of some new histone deacetylases inhibitors].

To explore novel histone deacetylase (HDAC) inhibitors with anti-tumor activity, twelve target compounds were synthesized, and their structures were confirmed by 1H NMR, MS and elemental analyses. Evaluation results in vitro showed that compound Ia exhibited potent inhibition against HDAC and is worth for further investigation. And compounds IIa, IIb, IIIa-IIIi possessed moderate HDAC inhibitory activity.

[Strategy of molecular drug design: activity and druggability].

Intrinsic activity and druggability represent two essences of innovative drugs. Activity is the fundamental and core virtue of a drug, whereas druggability is essential to translate activity to therapeutic usefulness. Activity and druggability are interconnected natures residing in molecular structure.

The synthesis of puerarin derivatives and their protective effect on the myocardial ischemia and reperfusion injury.

Puerarin is a naturally occurring isoflavone and is frequently used for the treatment of cardiovascular symptoms in China. By the structural modification of the puerarin molecule at different positions, seven new puerarin derivatives were obtained, and their cardioprotective activities (in vitro and in vivo) were respectively evaluated. The finding that the activities of 3 and 8 markedly exceeded puerarin suggested that the acylated modification of phenolic hydroxyl at C-7 in the puerarin molecule may improve the cardioprotective activity, which will be an important reference for further structural optimization.

[Comparative pharmacophore analysis of dual dopamine D2/5-HT(2A) receptor antagonists].

Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.

[Design of multiple targeted drugs].

Drugs designed to act on individual molecular targets usually can not combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes. Increasingly, it is being recognised that a balanced modulation of several targets can provide a superior therapeutic effect and side effect profile compared to the action of a selective ligand. The multi-target drugs which impact multiple targets simultaneously are better at controlling complex disease systems and are less prone to drug resistance.

[Strategy of molecular drug design: dual-target drug design].

Physiology-based and target-based drug discovery constitutes two principal approaches in drug innovation, which are mutually complementary and collaborative. With the target-based approach, a lot of new molecular entities have been marketed as drugs. However, many complicated diseases such as cancer, metabolic disorders, and CNS diseases can not be effectively treated or cured with one medicine acting on a single target.

[Strategy of molecular drug design: hits, leads and drug candidates].

Hits, leads and drug candidates constitute three millstones in the course of drug discovery and development. The definition of drug candidates is a critical point in the value chain of drug innovation, which not only differentiates the research and development stages, but more importantly, determines the perspective and destiny of the pre-clinical and clinical studies. All outcomes from the development stage are actually attributed to the chemical structure of candidates.

[Strategy of molecular design of drugs: the unification of macro-properties and micro-structures of a molecule].

The interaction of a drug with the organism involves both the disposition of a drug by the organism and the action of a drug on the organism. The disposition of various exogenous substances, including drugs, complies with general rules. The underlying physical and chemical changes to different drugs in view of time and space, i.

Synthesis and anti-diabetic activity of (RS)-2-ethoxy-3-{4-[2-(4-trifluoro-methanesulfonyloxy-phenyl)-ethoxy]-phenyl}-propionic acid.

Aim: To synthesize and study the anti-diabetic activity of (RS)-2-ethoxy-3-{4-[2-(4-trifluoromethanesulfonyloxy-phenyl)-ethoxy]-phenyl}-propionic acid (compound I).

Methods: Compound I was prepared in 6 steps, using 4-(2-hydroxy-ethyl)-phenol as the starting material. The in vitro selectivity and potency of target compound I, rosiglitazone and WY-14643 on human PPARalpha and PPARgamma were determined in reporter gene assays.

Formation of 4'-carboxyl acid metabolite of imrecoxib by rat liver microsomes.

Aim: Imrecoxib is a novel and moderately selective COX-2 inhibitor. The aim of the present in vitro investigation was to study the formation of the major metabolite 4'-carboxylic acid imrecoxib (M2) and identify the enzyme(s) involved in the reaction.

Methods: The formation of M2 was studied in rat liver cytosol in the absence or presence of liver microsome.

Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib.

Aim: To investigate the in vitro metabolism of imrecoxib in rat liver microsomes and to identify the cytochrome P450 (CYP) forms involved in its metabolism.

Methods: Liver microsomes of Wistar rats were prepared using an ultracentrifuge. The in vitro metabolism of imrecoxib was studied by incubation with rat liver microsomes.

[Using distance comparison method to build pharmacophore model of epidermal growth factor receptor inhibitors].

Objective: To build 3D-pharmacophore model of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors using distance comparisons method and design novel EGFR inhibitors.

Methods: Thirteen typical EGFR inhibitors were selected, and their biologically active conformations were obtained by using DOCK5.0 program, then 3D-pharmacophore model of EGFR inhibitors was built using distance comparisons method.

Imrecoxib: a novel and selective cyclooxygenase 2 inhibitor with anti-inflammatory effect.

Aim: To investigate the inhibitory effect of imrecoxib, a synthetic compound of completely new structure, on cyclooxygenase 1 (COX-1) and 2 (COX-2) and its anti-inflammatory effect in vivo.

Methods: The inhibitory effects of imrecoxib on cyclooxygenase 1 and 2 were studied using whole cell assay with murine peritoneal macrophages induced by calcimycin and LPS. The inhibitory effects of imrecoxib on mRNA level of COX-1 and COX-2 in human macrophage cell line U937 were detected by reverse transcription polymerase chain reaction (RT-PCR) analysis.