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Fibrosis is a disease that damages organs and even causes death. Because of the complicated pathogenesis, the development of drugs for fibrosis is challenging. In the lysophosphatidic acid receptor type 1 (LPA1) signaling pathway, LPA1 and its downstream Rho-associated coiled-coil forming protein kinase (ROCK) are related to the process of fibrosis. Targeting LPA1 signaling pathway is a potential strategy for the treatment of fibrosis.This review describes the process of fibrosis mediated by the LPA1 signaling pathway and then summarizes LPA1 antagonist patents reported since 2010 and ROCK inhibitor patents since 2017 according to their scaffolds based on the Cortellis Drug Discovery Intelligence database. Information on LPA1 antagonists entering clinical trials is integrated.Over the past decade, a large number of antagonists targeting the LPA1 signaling pathway have been patented for fibrosis therapy. A limited number of compounds have entered clinical trials. Different companies and research groups have used different scaffolds when designing compounds for fibrosis therapy. Therefore, LPA1 and ROCK are competitive targets for the development of new therapies for fibrosis to provide a potential treatment method for fibrosis in the future.

Fibrosis is a serious disease that occurs in many organs, such as kidney, liver and lung. The deterioration of these organs ultimately leads to death. Due to the complex mechanisms of fibrosis, research and development of antifibrotic drugs is difficult. One solution is to focus on core pathways, one of which is the TGF-β signaling pathway. In virtually every type of fibrosis, TGF-β signaling is recognized as a critical pathway.This review discusses patents on active molecules related to the TGF-β signaling. Molecules targeting components related to the activation of TGF-β are introduced. Several strategies preventing signal propagation from active TGF-β to downstream targets are also introduced, including TGF-β antibodies, TGF-β ligand traps, and inhibitors of TGF-β receptor kinases. Finally, molecules affecting downstream targets in both canonical and noncanonical TGF-β signaling pathways are described.Since the approval of pirfenidone, targeting TGF-β signaling has been anticipated as an effective therapy for fibrosis. The potential of this therapy has been further supported by emerging patents on the TGF-β signaling. This pathway can be entirely inhibited, from the activation of TGF-β to downstream signaling. Inhibiting TGF-β signaling is expected to provide more effective treatments for fibrosis.

Graphical abstract, Cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) is a negative innate immune checkpoint signaling pathway that restrains immunosurveillance and immune clearance, and thus has aroused wide interest in cancer immunotherapy. Blockade of the CD47/SIRPα signaling pathway shows remarkable antitumor effects in clinical trials. Currently, all inhibitors targeting CD47/SIRPα in clinical trials are biomacromolecules. The poor permeability and undesirable oral bioavailability of biomacromolecules have caused researchers to develop small-molecule CD47/SIRPα pathway inhibitors. This review will summarize the recent advances in CD47/SIRPα interactions, including crystal structures, peptides and small molecule inhibitors. In particular, we have employed computer-aided drug discovery (CADD) approaches to analyze all the published crystal structures and docking results of small molecule inhibitors of CD47/SIRPα, providing insight into the key interaction information to facilitate future development of small molecule CD47/SIRPα inhibitors.

Aim: Descriptors of molecules are important in the discovery of lead compounds. Most of these descriptors are used to represent molecular structures, although structural formulas are the most intuitive representation. Convolutional neural networks (ConvNets) are effective for managing intuitive information. Results/methodology: Convolutional neural networks (ConvNets) based on two-dimensional structural formulas were used for the preliminary screening of CDK4 inhibitors. After supervised learning of our homemade dataset, our models screened out ten approved drugs, including indocyanine green and candesartan cilexetil, with IC50 values of 2.0 and 5.2 μM, respectively. Conclusion: Depending only on intuitive information, the developed method was shown to be feasible, thus providing a new method of lead compound discovery.

Ethnopharmacological relevance Huiyang Shengji formula (HSF) is a compound Chinese herbal medicine prescription, and has long been used for treating chronic non-healing wounds. Aim of the study The purpose of this study was to provide new insight into molecular mechanisms of healing effects of the HSF treatments. Materials and methods We established a rat diabetic skin ulcer (DSU) model, and assessed healing effects of four HSF treatments on DSUs by calculating wound healing rates and immunohistochemical detection of the expressions of angiogenesis-related factors in the model rats (Mod) relative to normal rats (Nor), including Huiyang extract (HE), Shengji extract (SE), Huiyang Shengji extract (HSE) and HSE associated with acupuncture (Ac-HSE). We then performed NMR-based metabolomic analyses on skin tissues of the Nor, Mod, HSE-treated, Ac-HSE-treated rats to address metabolic mechanisms underlying these effects. Results These treatments up-regulated expressions of two angiogenesis-related factors VEGF and CD31, and improved efficacy of healing DSUs, in which HSE and Ac-HSE exhibited the most significant effects. Compared with Mod, HSE and Ac-HSE groups shared four characteristic metabolites (lactate, histidine, succinate and acetate) and four significantly altered metabolic pathways with Nor. Both HSE and Ac-HSE treatments could partly reverse the metabolically disordered pathological state of DSUs to the normal state. They might improve wound healing through promoting glucose metabolism, BCAAs metabolism, and enhancing antioxidant capacity and angiogenesis in DSU tissues. Ac-HSE significantly enhanced wound healing rates compared to HSE, potentially owing to significant capacities of enhancing anti-oxidation and angiogenesis and interfering three more metabolic pathways. Conclusions This work provides a mechanistic understanding of the healing effects of the HSE and Ac-HSE treatments on DSUs, is of benefit to improvements of the HSF treatments for clinically healing chronic non-healing wounds.

Introduction: Artificial intelligence systems based on neural networks (NNs) find rules for drug discovery according to training molecules, but first, the molecules need to be represented in certain ways. Molecular descriptors and fingerprints have been used as inputs for artificial neural networks (ANNs) for a long time, while other ways for describing molecules are used only for storing and presenting molecules. With the development of deep learning, variants of ANNs are now able to use different kinds of inputs, which provide researchers with more choices for drug discovery. Areas covered: The authors provide a brief overview of the applications of NNs in drug discovery. Combined with the characteristics of different ways for describing molecules, corresponding methods based on NNs provide new choices for drug discovery, including de novo drug design, ligand-based drug design, and receptor-based drug design. Expert opinion: Various ways for describing molecules can be inputs of NN-based models, and these models achieve satisfactory results in metrics. Although most of the models have not been widely applied and tested in practice, they can be the basis for automatic drug discovery in the future.

Introduction: Quorum sensing (QS) is a cell density-dependent phenomenon in which specific pathways are activated after autoinducers (AIs) outside the microorganism reach a threshold concentration. QS creates a positive feedback loop that induces a cascade of gene expression and causes biofilm formation, virulence and sporulation. QS signals are diverse, acyl-homoserine lactone (AHL), AI peptide (AIP) and AI-2 are three major categories of QS signals. QS inhibitors (QSIs) can disrupt or prevent the formation of biofilm and reduce virulence while exerting less selective pressure on the bacteria, suggesting that QSIs are potential alternatives for antibiotics. Areas covered: This review summarized the pertinent patents on QS inhibition available from 2014 to 2018. The authors analyze these patents and provided an overview of them and their potential applications. Expert opinion: The main strategy for QS inhibition is to use the analogues of various QS signals to block downstream signal transducers. The inactivation of signal molecules or the stimulation of the immune response is also attractive strategies to inhibit QS. However, additional clinical trials are needed to assess their efficacy in mammals. In sum, QS inhibition can reduce the virulence of bacteria without affecting their growth or killing them and the reduced pressure may minimize the increasingly resistance.

Cellular senescence is a physiological process reacting to stimuli, in which cells enter a state of irreversible growth arrest in response to adverse consequences associated with metabolic disorders. Molecular mechanisms underlying the progression of cellular senescence remain unclear. Here, we established a replicative senescence model of human umbilical vein endothelial cells (HUVEC) from passage 3 (P3) to 18 (P18), and performed biochemical characterizations and NMR-based metabolomic analyses. The cellular senescence degree advanced as the cells were sequentially passaged in vitro, and cellular metabolic profiles were gradually altered. Totally, 8, 16, 21 and 19 significant metabolites were primarily changed in the P6, P10, P14 and P18 cells compared with the P3 cells, respectively. These metabolites were mainly involved in 14 significantly altered metabolic pathways. Furthermore, we observed taurine retarded oxidative damage resulting from senescence. In the case of energy deficiency, HUVECs metabolized neutral amino acids to replenish energy, thus increased glutamine, aspartate and asparagine at the early stages of cellular senescence but decreased them at the later stages. Our results indicate that cellular replicative senescence is closely associated with promoted oxidative stress, impaired energy metabolism and blocked protein synthesis. This work may provide mechanistic understanding of the progression of cellular senescence.

Fibrotic diseases have become a major cause of death in the developed world. AdipoR1 agonists are potent inhibitors of fibrotic responses. Here, we focused on the in silico identification of novel AdipoR1 peptide agonists. A homology model was constructed to predict the 3D structure of AdipoR1. By docking to known active peptides, the putative active site of the model was further explored. A virtual screening study was then carried out with a set of manually designed peptides using molecular docking. Peptides with high docking scores were then evaluated for their anti-fibrotic properties. The data indicated that the novel peptide Pep70 significantly inhibited the proliferation of hepatic stellate cells (HSC) and NIH-3T3 cells (18.33% and 27.80%) and resulted in favouring cell-cycle arrest through increasing the accumulation of cells in the G0/G1 phase by 17.08% and 15.86%, thereby reducing the cell population in the G2/M phase by 11.25% and 15.95%, respectively. Additionally, Pep70 exhibited the most marked suppression on the expression of α-smooth muscle actin (α-SMA), collagen type I alpha1 (COL1A1) and TGF-β1. Therefore, the peptide Pep70 was ultimately identified as an inhibitor of fibrotic responses and as a potential AdipoR1 agonist.

Aim: CDK4/6 have critical roles in the early stage of the cell cycle. CDK2 acts later in the cell cycle and has a considerably broader range of protein substrates, some of which are essential for normal cell proliferation. Therefore, increasing the selectivity of cyclin-dependent kinase (CDK) inhibitors is critical. Methodology: In this study, we construct a versatile, specific CDK4 pharmacophore model that not only matches well with 8119 of the reported 9349 CDK4/6 inhibitors but also differentiates from the CDK2 pharmacophore. Results & Conclusion: we demonstrate the activity and selectivity determinants of CDK4/6 selective inhibitors based on the CDK4 pharmacophore model. Finally, we propose the future optimization strategy for CDK4/6 selective inhibitors, providing a theoretical basis for further research and development of CDK4/6 selective inhibitors.

Aim: Parathyroid hormone-1 receptor (PTH1R) is a member of B G protein-coupled receptors. The agonistic activation of the PTH1R results in the production and secretion of osteoclast-stimulating cytokines while antagonists may be used to treat bone metastases, hypercalcemia, cachexia and hyperparathyroidism. Results: We built pharmacophore models and investigated the characteristics of PTH1R agonists and antagonists. The agonist model consists of three hydrophobic points, one hydrogen bond acceptor and one positive ionizable point. The antagonist model consists of one hydrogen bond donor and three hydrophobic points. Conclusion: The features of the two models are similar, but the hydrogen bond acceptor, which is the main difference between PTH1R agonists and antagonists, suggests it may be essential for the agonist.

The emergence of antibiotic-resistant Mycobacterium Tuberculosis (Mtb) infections compels new treatment strategies, of which targeting trans-translation is promising. During the trans-translation process, the ribosomal protein S1 (RpsA) plays a key role, and the Ala438 mutant is related to pyrazinamide (PZA) resistance, which shows its effects after being hydrolysed to pyrazinoic acid (POA). In this study, based on the structure of the RpsA C-terminal domain (RpsA-CTD) and POA complex, new compounds were designed. After being synthesized, the compounds were tested in vitro with saturation transfer difference (STD), fluorescence quenching titration (FQT) and chemical shift perturbation (CSP) experiments. Finally, six of the 17 new compounds have high affinity for both RpsA-CTD and its Ala438 deletion mutant. The active compounds provide new choices for targeting trans-translation in Mtb, and the analysis of the structure-activity relationships will be helpful for further structural modifications based on derivatives of 2-((hypoxanthine-2-yl)thio)acetic acid and 2-((5-hydroxylflavone-7-yl)oxy)acetamide.

Introduction: Fibrotic disorders are a leading cause of morbidity and mortality; hence effective treatments are still vigorously sought. AdipoRs (AdipoR1 and Adipo2) are responsible for the antifibrotic effects of adiponectin (APN). APN exerts antifibrotic effects by binding to its receptors. APN concentration and AdipoR expression are closely associated with fibrotic disorders. Decreased AdipoR expression may reduce APN-AdipoR signaling, while the upregulation of AdipoR expression may restore the anti-fibrotic effects of APN. Loss of APN signaling exacerbates fibrosis in vivo and in vitro. Areas covered: We assess the relationship between APN and fibrotic disorders, the structure of receptors for APN and the pathways accounting for APN or its analogs blocking fibrotic disorders. This article also discusses designed APN products and their therapeutic prospects for fibrotic disorders. Expert opinion: AdipoRs have a critical role in blocking fibrosis. The development of small-molecule agonists toward this target represents a valid drug development pathway.

P2Y12 receptor becomes a favorable target for therapeutic antiplatelet agents. Reversible P2Y12 receptor antagonists have more benefits than the irreversible ones on rapid absorption, onset of action and higher inhibition of platelet aggregation. As potent reversible P2Y12 receptor antagonists, piperazinyl-glutamate-pyridines exhibit a significant improvement in efficacy while maintaining a better safety profile than the irreversible ones. In this study, we developed a 3D pharmacophore model with r 2 = 0.966 based on a set of piperazinyl-glutamate-pyridines showing the important pharmacophore features (one hydrogen bond acceptor, one hydrogen bond donor, one ring aromatic and one hydrophobic feature) which is necessary for reversible P2Y12 receptor antagonists. The obtained pharmacophore models were validated by using well-known methodologies such as test molecules and Fischer’s randomization method. A docking study was also performed based on the recently released P2Y12 receptor crystal structure (PDB ID: 4NTJ) which revealed key residues (Tyr105, His 187 and Lys280) in the receptor–ligand interaction. The docking results were well in agreement with the pharmacophore model that raised the model’s reliability. The pharmacophore model was further confirmed by estimating the activity of six known drugs which can distinguish the reversible P2Y12 receptor antagonists from the irreversible ones. The results of our study provide confidence for the utility of the selected chemical features to retrieve further compounds as reversible P2Y12 receptor antagonists.

Ribosomal protein S1 (RpsA) has been identified as a novel target of pyrazinoic acid (POA), which is the active form of pyrazinamide (PZA), in vivo. RpsA plays a crucial role in trans-translation, which is widespread in microbes. In our investigation, we first described the discovery of promising RpsA antagonists for drug-resistant mycobacterium (MtRpsAd438A) and M. smegmatis, as well as wild-type M. tuberculosis. These antagonists were discovered via structure/ligand-based virtual screening approaches. A total of 21 targeted compounds were selected by virtual screening, combined scores, affinity, similarities and rules for potential as drugs. Next, the affinities of these compounds for three targeted proteins were tested in vitro by applying various technologies, including fluorescence quenching titration (FQT), saturation transfer difference (STD), and chemical shift perturbation (CSP) assays. The results showed that seven compounds had a high affinity for the targeted proteins. Our discovery set the stage for discovering new chemical entities (NCEs) for PZA-resistant tuberculosis and providing key residues for rational drug design to target RpsA.

A series of 14-deoxyandrographolide-19-oic acid and 14-deoxy-11,12 (or 14,15)-didehydroandrographolide-19-oic acid derivatives were designed, synthesized and screened in vitro against the mouse fibroblast cell lines NIH-3T3. Thirteen compounds 8a-f, 14a-c, 14e-f, and 18a-b were found to exhibit better anti-fibrotic activities than andrographolide, with compounds 8b and 14e displaying best activity with IC50 values of 12.86 and 13.57 μM against NIH-3T3 respectively. Further anti-fibrotic investigation was performed in terms of PCR and western bolt analysis. Our study demonstrated that compounds 8b and 14e suppressed effectively the expression of α-smooth muscle actin, fibronectin and collagen in NIH-3T3. Preliminary structure-activity analysis revealed that 14-deoxygenation and 19-carboxylation of andrographolide could significantly improve its anti-fibrotic effect, which made 14-deoxyandrographolide-19-oic acid and 14-deoxy-11,12-didehydroandrographolide-19-oic acid promising leads for the development of new anti-fibrotic agents.

The cellular prion protein (PrP(C)) is a kind of cell-surface Cu(2+)-binding glycoprotein. The oligomerization of PrP(C) is highly related to transmissible spongiform encephalopathies (TSEs). Cu(2+) plays a vital role in the oligomerization of PrP(C), and participates in the pathogenic process of TSE diseases. It is expected that Cu(2+)-binding has different effects on the oligomerization of TSE-sensitive human PrP(C) (HuPrP(C)) and TSE-resistant rabbit PrP(C) (RaPrP(C)). However, the details of the distinct effects remain unclear. In the present study, we measured the interactions of Cu(2+) with HuPrP(C) (91-230) and RaPrP(C) (91-228) by isothermal titration calorimetry, and compared the effects of Cu(2+)-binding on the oligomerization of both PrPs. The measured dissociation constants (Kd) of Cu(2+) were 11.1 ± 2.1 μM for HuPrP(C) and 21.1 ± 3.1 μM for RaPrP(C). Cu(2+)-binding promoted the oligomerization of HuPrP(C) more significantly than that of RaPrP(C). The far-ultraviolet circular dichroism spectroscopy experiments showed that Cu(2+)-binding induced more significant secondary structure change and increased more β-sheet content for HuPrP(C) compared with RaPrP(C). Moreover, the urea-induced unfolding transition experiments indicated that Cu(2+)-binding decreased the conformational stability of HuPrP(C) more distinctly than that of RaPrP(C). These results suggest that RaPrP(C) possesses a low susceptibility to Cu(2+), potentially weakening the risk of Cu(2+)-induced TSE diseases. Our work sheds light on the Cu(2+)-promoted oligomerization of PrP(C), and may be helpful for further understanding the TSE-resistance of rabbits.

Aim: Resistance to conventional antibiotics has spurred interest in exploring new antimicrobial strategies. Suppressing quorum sensing within biofilm is a promising antimicrobial strategy. LasR in quorum sensing system of the Gram-negative bacteria, Pseudomonas aeruginosa, directly enhances virulence and antibiotic resistance, with QscR as its indirect suppressor, so targeting both of them can synergistically take the effect. Methodology/results: An in silico protocol combining pharmacophores with molecular docking was applied. Pharmacophores of QscR agonists and LasR antagonists were prepared for preliminary screening, followed by counter-screen using a pharmacophore model of LasR agonists and molecular docking of LasR. Four compounds with novel scaffolds were confirmed as potential biofilm inhibitors with preliminary experimental data. Conclusion: Novel biofilm inhibitors can be found with the method.

VEGF is an important signaling protein involved in both vasculogenesis and angiogenesis. As an essential receptor protein tyrosine kinase propagating cellular signal transduction processes, VEGFR-2 is a central target for drug discovery against tumor-associated angiogenesis. Since the autophosphorylation of VEGFR-2 represents a key step in this signal pathway that contributes to angiogenesis, the discovery of small molecule inhibitors that block this reaction has attracted great interest for novel drugs research and development. Advances in the understanding of catalytic cleft and the conformational changes of DFG motif have resulted in the development of small molecule inhibitors known as type I and type II. High-resolution crystal structures of various inhibitors in complex with the receptor offer an insight into the relationship among binding modes, inhibition mechanisms, activity, selectivity and resistance. To control selectivity, improve activity and introduce intellectual property novelty, the strategies for the further development are discussed through structural and conformational analysis in this review.

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is the only member of the lipocalin superfamily that displays enzymatic activity. It binds lipophilic ligands with high affinity and also can catalyze PGH2 to produce PGD2. Three cysteine residues, Cys65, Cys89, and Cys186 in L-PGDS, are conserved among all species, of which Cys89 and Cys186 residues form a disulfide bridge. In this study, we clarified the effects of thiol groups on the structure of the protein and investigated the structural significance of Cys residues of rat L-PGDS by site-directed mutagenesis. Four mutants were constructed by substituting Cys residues with alanine to identify the correct formation of disulfide bonds among these three residues. The effects of thiol groups on the structure of rat L-PGDS were also identified by these mutants. Analysis of HSQC experiments indicated that these enzymes were all properly folded with well defined tertiary structures. As the first step towards the 3-D nuclear magnetic resonance solution structure, we optimized expression of recombinant rat L-PGDS in Escherichia coli and established an efficient and economic purification protocol yielding large amounts of pure isotopically labeled rat L-PGDS. The results of assignments indicated that the wild-type rat L-PGDS obtained using this expression system was suitable for determination of 3-D nuclear magnetic resonance solution structure.

The cellular prion protein (PrP(C)) is a kind of cell-surface Cu(2+)-binding glycoprotein. The oligomerization of PrP(C) is highly related to transmissible spongiform encephalopathies (TSEs). Cu(2+) plays a vital role in the oligomerization of PrP(C), and participates in the pathogenic process of TSE diseases. It is expected that Cu(2+)-binding has different effects on the oligomerization of TSE-sensitive human PrP(C) (HuPrP(C)) and TSE-resistant rabbit PrP(C) (RaPrP(C)). However, the details of the distinct effects remain unclear. In the present study, we measured the interactions of Cu(2+) with HuPrP(C) (91-230) and RaPrP(C) (91-228) by isothermal titration calorimetry, and compared the effects of Cu(2+)-binding on the oligomerization of both PrPs. The measured dissociation constants (Kd) of Cu(2+) were 11.1 ± 2.1 μM for HuPrP(C) and 21.1 ± 3.1 μM for RaPrP(C). Cu(2+)-binding promoted the oligomerization of HuPrP(C) more significantly than that of RaPrP(C). The far-ultraviolet circular dichroism spectroscopy experiments showed that Cu(2+)-binding induced more significant secondary structure change and increased more β-sheet content for HuPrP(C) compared with RaPrP(C). Moreover, the urea-induced unfolding transition experiments indicated that Cu(2+)-binding decreased the conformational stability of HuPrP(C) more distinctly than that of RaPrP(C). These results suggest that RaPrP(C) possesses a low susceptibility to Cu(2+), potentially weakening the risk of Cu(2+)-induced TSE diseases. Our work sheds light on the Cu(2+)-promoted oligomerization of PrP(C), and may be helpful for further understanding the TSE-resistance of rabbits.

Caseinolytic protein proteases (ClpP) are large oligomeric protein complexes that contribute to cell homeostasis as well as virulence regulation in bacteria. Inhibitors of ClpP can significantly attenuate the capability to produce virulence factors of the bacteria. In this work, we developed a workflow to expand the chemical space of potential ClpP inhibitors based on a set of β-lactones. In our workflow, an artificial pharmacophore model was generated based on HipHop and HYPOGEN method. A de novo compound library based on molecular fingerprints was constructed and virtually screened by the pharmacophore model. The results were further investigated by molecular docking study. The workflow successfully achieved potential ClpP inhibitors. It could be applied to design more novel potential ClpP inhibitors and provide theoretical basis for the further optimization of the hit compounds.

As increasing drug-resistance poses an emerging threat to public health, the development of novel antibacterial agents is critical. We developed a workflow consisting of various methods for de novo design. In the workflow, 2D-QSAR model based on molecular fingerprints was constructed to extract the bioactive molecular fingerprints from a data set of DNA–gyrase inhibitors with new structure and mechanism. These fingerprints were converted into molecular fragments which were recombined to generate compound library. The new compound library was virtually screened by LigandFit and Gold docking, and the results were further investigated by pharmacophore validation and binding mode analysis. The workflow successfully achieved a potential DNA–gyrase inhibitor. It could be applied to design more novel potential DNA–gyrase inhibitors and provide theoretical basis for further optimization of the hit compounds.

We have previously shown that a recombinant human PTH fragment, Pro-Pro-[Arg11] hPTH (1-34)-Pro-Pro-Asp (hPTH'), could be a potentially better and more cost-effective therapeutic agent than PTH (1-34) on osteoporosis. In this report, we characterized the solution conformations of hPTH' by NMR spectroscopy and modeled the interactions between the hPTH' and the PTH receptor. By comparing it with PTH (1-34) structures and their respective interactions with the PTH receptor, we identified two segments of helix extending from Ile5 to Met8 and from Glu22 to Gln29 with a divided kink between the two helixes around Arg20. Mutated arginine makes hPTH' fill the receptor cavity better as well as forms hydrogen bonds with Val193. Understanding the ligand receptor interactions will help us design small molecules to better mimic the activities of PTH.