FBDD and drugs originated from FBDD / 药学学报

The binding of small molecule drugs to targets is mostly through non-covalent bonds, and hydrogen bond, electrostatic, hydrophobic and van der Waals interactions function to maintain the binding force. The more these binding factors lead to strong bindings and high activities. However, it is often accompanied by the increase of molecular size, resulting in pharmacokinetic problems such as membrane penetration and absorption, as well as metabolism, which ultimately affects the drug success. Fragment-based drug discovery (FBDD) is to screen high-quality fragment library to find hits. Combine with structural biology, FBDD generates lead compounds by means of fragment growth, linking and fusion, and finally drug candidates by the optimization operation. During the value chain FBDD is closely related to structure-based drug discovery (SBDD). In this paper, the principle of FBDD is briefly described by several launched drugs.

On improving the activity and selectivity of small molecule drugs / 药学学报

Although small molecule drugs (SMD) are still mainstream for the treatment of diseases, large molecule biologicss of many advantages, pose a challenge to the further discovery and use of SMD. The advantages of SMD are the convenience of oral administration and good patient compliance. However, the challenge with SMD is to integrate the PD, PK, selectivity and safety into a chemical structure. Because of their small size and surface area they often bind to various proteins, and off-target actions can cause adverse reactions. In this sense, selectivity is critical. Based upon target as the core to construct a chemical structure, it is necessary to consider the requirements of all the attributes, but achievement of the full-dimensional optimization is difficult. Modern drug discovery has been greatly enhanced by molecular biology and structural biology, and new strategies and technologies have emerged, which have created many successful medicines. For example, under the guidance of structural biology, covalent binding drugs connect moderate "electrophilic warheads" to the appropriate positions of molecules, and upon binding to their targets the electrophiles are irreversibly linked to the target by covalent bonds. Molecular biology can be directly applied to the development of antibody-coupled drugs (ADC). The antibody (A) acts as a carrier and a guide (for PK), and carries toxic molecules (D) into cancer cells, thus playing a killing role (for PD). The separate pharmacodynamic and pharmacokinetic entities are coupled (C) by linkers. PROTACs are also bifunctional molecules, which recruit a target protein and ubiquitin ligase E3 to form a ternary complex, which then acts as a catalyst to ubiquitinate the target protein and lead to degradation by the proteasome. In addition, in recent years, the combination of two fixed-dose drugs has improved selectivity, safety, and long-term benefit with many severe diseases, and can be regarded as an innovative strategy of physical combination. This review discusses some successful examples to briefly present the principles from the perspective of medicinal chemistry and therapeutic application.

Perspective of CADD and AIDD in medicinal chemistry / 药学学报

Artificial intelligence-aided drug discovery (AIDD) is a new version of computer-aided drug discovery (CADD). AIDD is featured in significantly promoting the performance of conventional CADD. AI markedly enhances the learning ability of CADD. In the 1960s, CADD was established from conventional QSAR approaches, which mainly used regression approaches to derive substructure-activity relationship for compounds with a common scaffold, and guide drug molecular design, figure out the binding features of drugs, and identify potential drug targets. Since the 1990s, structural biology has provided three-dimensional structures of drug targets, enabling drug discovery based on target structure (SBDD), fragment-based drug discovery (FBDD), and structure-based virtual screening (SBVS) with CADD approaches. In the past 30 years, many first in class (FIC) and best in class (BIC) drugs were discovered with CADD. Now, AIDD will further revolutionize CADD by reducing human interventions and mining big chemical and biological data. It is expected that AIDD will significantly enhance the abilities of CADD, virtual screening and drug target identification. This article tries to provide perspectives of CADD and AIDD in medicinal chemistry with case studies.

Drug discovery from viewpoint of medicinal chemists / 药学学报

Taking patient needs as the core and realizing clinical value as the guidance are the purpose and path of drug discovery. Whether the first-in-class drug or follow-on drugs are all to meet the demands of patients for drugs that are not treatable or more safe and effective. In order to realize clinical value, innovative drugs driven by basic biological research include three elements: understanding the molecular mechanism of pathogenesis; Grasping the microscopic features of the disease; clarifying the mechanism of action of drugs. The interrelation among the three is the translational medicine, and the medicinal chemistry plays an important role in the translations. That is, based on the results of basic research in biology/medicine, knowledge of the molecular mechanism of disease depends upon the establishment of various in vitro/in vivo models to find the key node and molecular regulation for the treatment of disease. Combined with the knowledge of gene deletion and variation, proteomics, epigenetics and other technologies, the molecular mechanism of disease provides multi-molecular information on the level of gene, proteins, enzymes, receptors, ion channels and signal transduction for molecular drug design. Insight into the microscopic characteristics of diseases would deepen the understanding of the molecular mechanism of the pathogenesis, as well as provide a feasible scientific path for the creation of new drugs. When the molecular mechanism of disease and the action mechanism of drugs are clarified, we have a deeper and wider understanding of the application of existing drugs (or active compounds), and may offer new ideas for drug design and application. In this translational process the medicinal chemistry plays a key role which requires medicinal chemists to break through the habitual thinking and working mode, backtracking (upstream) to basic research and its achievements and applying to the direction of creating new drugs in time, as well as paying attention to the clinical requirements (downstream) and implementing the specific content of the transformation process for the R&D of innovative drugs.

Examples of biology-driven drug design / 药学学报

Pharmacological activity and drug likeness depend in principle upon the microscopic structure and macroscopic properties of drugs, which reside in their molecular structures. By means of medicinal chemistry the evolution of an active compound to a novel drug (NME) essentially makes the two pillars coexistence in one chemical structure, which either could merge as an intrinsic structure or connect from external fragments to each other with covalent bonds. Since the new millennium the advance in biology provides several knowledge and technologies, for example humanized monoclonal antibody, proteasome-ubiquitin system, allosteric modulation, natural macromolecules, structural biology, etc., for innovation of novel medicines. Taking several examples on marketed drugs or drug candidates in clinical trials, this article tries to concisely illustrate R & D conception of biology-driven drug design.

A brief analysis of bifunctional molecules / 药学学报

Selectivity of drug action is a determinant for wide therapeutic window and less adverse response. From the viewpoint of molecular structure the conception and strategy of drug design are mainly embodied in raising selectivity. For the target-based drug discovery it is crucial to precisely obliterate detrimental targets in dimension of time and space, so as to efficaciously translate the in vitro active compounds into in vivo therapeutic medicines. To realize this translation drug molecules must be accurately transported to and destroy the harmful targets. To this end, chemical structures of drugs must be manipulated in multiple dimensions. This article attempts to concisely describe several kinds of bifunctional molecules for raising selectivity from the standpoint of medicinal chemistry. The bifunctionality of antibody-drug conjugates (ADCs) involves in the guidance and carrier of the antibody to guide ADC and reach to target cells, and simultaneously injury quality of the toxin moiety of ADC interacts with and destroys targets. Based upon target 3D structures design of irreversible inhibitors consist in connecting an appropriate electrophilic moiety to a well-defined ligand to endow the molecule with an additional ability to covalently bond to a specific amino acid residue. Hydrophobic tag (HyT), proteosis-targeting chimera (PROTAC), and degradation tag (dTAG) are new developed technologies, which are structurally characterized by bifunctionality, and mechanistically these compounds are capable of recruiting protein of interest (POI), inducing protein-protein interaction (PPI), and cleaving POI. In spite of large molecular size and the bottleneck of pharmacokinetic and physicochemical properties these technologies still have broad development prospect owing to high selectivity and wide adaptations.

On the innovation of follow-on drugs / 药学学报

Follow-on drug approach is to follow-up and make-up of the innovation of pioneering drugs. Since the millennium new molecular entities (NME) have experienced ample optimization, and the patents have claimed in wide ranges, as well as the drug administration requires NME being superior or non-inferior to the existing drugs of the same class. These situations have made the space of follow-on drug innovation narrow and smaller than before. The follow-on drug approach can be concisely differentiated into two aspects:one is to start from the chemistry of small molecules, which are performed with a niche-targeting manipulation to optimize the safety, efficacy and (or) convenience for dose superior to the existing drugs; another proceeds with the macromolecule targets. Based on the knowledge of the mechanism of action or of target mutation, active compounds are constructed through complementary binding or by the reaction mechanism. In this article successful examples are briefly described to illustrate the features of follow-on drug approach.

On the molecular drug design from viewpoint of precision medicine / 药学学报

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. PM and drug research/application are interdependent and promote each other. Aimed at precision medicine, drug discovery and development involve well-known contents:the discovery and validation of targets, the association between target functions and indications (proof of concept), lead discovery and optimization, the association between preclinical investigations and clinical trials, the lean of industrialization and pharmacoeconomics. At the molecular level the therapeutic efficacy originates from the interactive binding between specific atoms or groups of the drug molecule and the complementary atoms or groups of the macromolecular target in three-dimensional space. The strict arrangement of such critical atoms, groups, or fragments reflect specific features for a precise binding to the corresponding target. An alteration of amino acid residues in mutational targets leads to the change in conformation of the target protein, and an accurate structure of drug is necessary for binding to the mutant species and avoiding off-targeting effect. For the tailoring of clinical treatment to the individual patient design and development of various new molecular entities are critical for treatment choice according to the molecular features of biological markers of patients. This article provides some examples and methods of drug design and development in the new period.

Concise analysis for innovation of pioneering and follow-on drugs / 药学学报

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 fo llowing 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. This article concisely analyzes several critical aspects of current status of drug discovery.

Drug innovation and reverse thinking / 药学学报

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. The innovation of first-in-class drugs is characterized by a high risk throughout the whole process. To achieve initiative and uniqueness of drug discovery, the strategy and method of the inverse thinking might be a feasible way, because the inertial and conformity thinkings in drug discovery normally lead to ensemble with similar drug category. However, the study from the flipside or opposite of things (e.g. targets or effects) brand new routes might be opened. This article is to describe the strategy of reverse thinking in drug discovery by some examples including opioid receptor antagonist eluxadoline, HSP90 activator, hERG channel agonist, covalent drugs, and ultra-small drugs.

Application of temperature sensitive yeast models with definite target in the screening of potential human Pin1 inhibitors / 药学学报

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. In vitro, 8-11 inhibited purified Pin1 enzyme activity with IC50 of (10.40 +/- 1.68) micromol x L(-1), induced G1 phase arrest and apoptosis, showed inhibitory effects on a series of cancer cell proliferation, reduced Cyclin D1 expression, was defined as reciprocally matched for protein-ligand complex in virtual docking analysis and reduced cell migration ability. In vivo, we could observe reduction of tumor volume after treatment with 8-11 in xenograft mice compared with vehicle DMSO treatment. Altogether, these results provide for the first time the involvement of 8-11 in the anticancer activity against Pin1.

Challenges and strategies of drug innovation / 药学学报

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. On the macro level, market prospects, capital required, risk assessment, necessary human resources, etc. need to be evaluated critically. For execution, drug candidates need to be optimized in multiple properties such as potency, selectivity, pharmacokinetics, safety, formulation, etc., all with the constraint of finite amount of time and resources, to maximize the probability of success in clinical development. Drug discovery is enormously complicated, both in terms of technological innovation and organizing capital and other resources. A deep understanding of the complexity of drug research and our competitive edge is critical for success. Our unique government-enterprise-academia system represents a distinct advantage. As a new player, we have not heavily invested in any particular discovery paradigm, which allows us to select the optimal approach with little organizational burden. Virtue R&D model using CROs has gained momentum lately and China is a global leader in CRO market. Essentially all technological support for drug discovery can be found in China, which greatly enables domestic R&D efforts. The information technology revolution ensures the globalization of drug discovery knowledge, which has bridged much of the gap between China and the developed countries. The blockbuster model and the target-centric drug discovery paradigm have overlooked the research in several important fields such as injectable drugs, orphan drugs, and following high quality therapeutic leads, etc. Prejudice against covalent ligands, prodrugs, nondrug-like ligands can also be taken advantage of to find novel medicines. This article will discuss the current challenges and future opportunities for drug innovation in China.

Ligand efficiency and lead optimization / 药学学报

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. On the basis of the describing parameters of activity and druggability, this overview deals with the roles of thermodynamic signatures and binding kinetics of drug-receptor interactions in optimizing quality of compounds, signifying the significance in optimization of microscopic structures for drug discovery.

Modification of natural products for drug discovery / 药学学报

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. Natural products are a rich source of therapeutic drugs. As compared to synthetic molecules, natural products are unusually featured by structural diversity and complexity more stereogenic centers and fewer nitrogen or halogen atoms. Naturally active substances usually are good lead compounds, but unlikely meet the demands for druggability. Therefore, it is necessary to modify and optimize these structural phenotypes. Structural modification of natural products is intent to (1) realize total synthesis ready for industrialization, (2) protect environment and resources, (3) perform chemical manipulation according to the molecular size and complexity of natural products, (4) acquire novel structures through structure-activity relationship analysis, pharmacophore definition, and scaffold hopping, and (5) eliminate unnecessary chiral centers while retain the bioactive configuration and conformation. The strategy for structural modification is to increase potency and selectivity, improve physico-chemical, biochemical and pharmacokinetic properties, eliminate or reduce side effects, and attain intellectual properties. This review elucidates the essence of natural products-based drug discovery with some successful examples.

Drug promiscuity / 药学学报

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. Drug promiscuity originates from protein promiscuity. In order to accommodate, metabolize and excrete various endo- and exogenous substances, protein acquired the capability during evolution to adapt a wide range of structural diversity, and it is unnecessary to reserve a specific protein for every single ligand. The structures of target proteins are integration of conservativity and diversity. The former is represented by the relatively conservative domains for secondary structures folding, which leads to overlapping in ligand-binding and consequent cross-reactivity of ligands. Diversity, however, embodies the subtle difference in structures. Similar structural domain may demonstrate different functions due to alteration of amino acid sequences. The phenomenon of promiscuity may facilitate the "design in" of multi-target ligands for the treatment of complicated diseases, whereas it should be appropriately handled to improve druggability. Therefore, one of the primary goals in drug design is to scrutinize and manipulate the "merits and faults" of promiscuity. This review discusses the application of promiscuity in drug design for receptors, enzymes, ion channels and cytochrome P450. It also briefly describes the methods to predict ligand promiscuity based on either target or ligand structures.

Strategy of molecular drug design: activity and druggability / 药学学报

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 pharmaceutical, pharmacokinetic and pharmacodynamic phases in vivo can be conceived as an overall exhibition of activity and druggability. Druggability actually involves all properties, except for intrinsic activity, of a drug. It embraces physico-chemical, bio-chemical, pharmacokinetic and toxicological characteristics, which are intertwined properties determining the attributes and behaviors of a drug in different aspects. Activity and druggability of a drug are endowed in the chemical structure and reflected in the microscopic structure and macroscopic property of a drug molecule. The lead optimization implicates molecular manipulation in multidimensional space covering activity, physicochemistry, biochemistry, pharmacokinetics and safety, and embodies abundant contents of medicinal chemistry.

Synthesis and activity of some new histone deacetylases inhibitors / 药学学报

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: dual-target drug design / 药学学报

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. As simultaneous intervention of two (or multiple) targets relevant to a disease has shown improved therapeutic efficacy, the innovation of dual-target drugs has become an active field. Dual-target drug can modulate two receptors, inhibit two enzymes, act on an enzyme and a receptor, or affect an ion channel and a transporter. From viewpoint of molecular design, there are three approaches to construct a dual-target drug molecule. A connective molecule can simply be realized by combining two active molecules or their pharmacophores with a linker; while an integrated molecule comes into an entity either by fusing or by merging the common structural or pharmacophoric features of two active molecules, depending on the extent of the common features. The latter approach facilitates the reduction of molecular size and molecular weight and the optimal overlap between the pharmacodynamic and pharmacokinetic spaces, which will certainly elevate the probability of being a drug.

Design of multiple targeted drugs / 药学学报

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. Here, we compare the disadvantage of the selective ligands and the predominance of multi-targets drugs in detail and introduce the approaches of designing multiple ligands and the procedure of optimization particularly. A key challenge in the design of multiple ligands is attaining a balanced activity at each target of interest while simultaneously achieving a wider selectivity and a suitable pharmacokinetic profile. On this point, the multi-target approach represents a new challenge for medicinal chemists, pharmacologists, toxicologists, and biochemists.

Comparative pharmacophore analysis of dual dopamine D2/5-HT(2A) receptor antagonists / 药学学报

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.