Identification Of Potential Drug Targets Research Articles

Identification of potential drug targets for vascular dementia and carotid plaques by analyzing underlying molecular signatures shared by them.

BackgroundVascular dementia (VaD) and carotid atherosclerotic plaques are common in the elderly population, conferring a heavy burden on families and society. Accumulating evidence indicates carotid atherosclerotic plaques to be a risk factor for VaD. However, the underlying mechanisms for this association are mainly unknown.Materials and methodsWe analyzed temporal cortex gene expression data of the GSE122063 dataset and gene expression data of the GSE163154 dataset to identify commonly differentially expressed genes (DEGs). Then we performed functional enrichment analysis, immune cell infiltration and evaluation, correlation analysis between differentially expressed immune-related genes (DEIRGs) and immune cells, receiver operating characteristic (ROC) analysis, and drug-gene analysis.ResultsWe identified 41 overlapped DEGs between the VaD and carotid atherosclerosis plaque datasets. Functional enrichment analyses revealed that these overlapped DEGs were mainly enriched in inflammatory and immune-related processes. Immunocyte infiltration and evaluation results showed that M0 macrophages, M2 macrophages, and T cells gamma delta had a dominant abundance in carotid atherosclerosis plaque samples, and M0 macrophages showed a significantly different infiltration percentage between the early and advanced stage plaques group. Resting CD4 memory T cells, M2 macrophages, and naive B cells were the top three highest infiltrating fractions in VaD. Furthermore, B cells and NK cells showed a different infiltration percentage between VaD and matched controls. We identified 12 DEIRGs, and the result of correlation analysis revealed that these DEIRGs were closely related to differentially expressed immune cells. We identified five key DEIRGs based on ROC analysis. The drug-gene interaction analysis showed that four drugs (avacopan, CCX354, BMS-817399, and ASK-8007) could be potential drugs for VaD and carotid atherosclerotic plaques treatment.ConclusionCollectively, these findings indicated that inflammatory and immune-related processes be a crucial common pathophysiological mechanism shared by VaD and carotid plaques. This study might provide new insights into common molecular mechanisms between VaD and carotid plaques and potential targets for the treatment.

A Coccidia-Specific Phosphate Transporter Is Essential for the Growth of Toxoplasma gondii Parasites.

ABSTRACTToxoplasma gondii is an obligate intracellular parasite that acquires all necessary nutrients from the hosts, but the exact nutrient acquisition mechanisms are poorly understood. Here, we identified three putative phosphate transporters in T. gondii. TgPiT and TgPT2 are mainly on the plasma membrane, whereas TgmPT is localized to the mitochondrion. TgPiT and TgmPT are widely present and conserved in apicomplexan parasites that include Plasmodium and Eimeria species. Nonetheless, they are dispensable for the growth and virulence of Toxoplasma. TgPT2, on the other hand, is restricted to coccidia parasites and is essential for Toxoplasma survival. TgPT2 depletion led to reduced motility and invasion, as well as growth arrest of the parasites both in vitro and in vivo. Both TgPiT and TgPT2 have phosphate transport activities and contribute to parasites’ inorganic phosphate (Pi) absorption. Interestingly, the Pi importing activity of Toxoplasma parasites could be competitively inhibited by ATP and AMP. Furthermore, direct uptake of 32P-ATP was also observed, indicating the parasites’ ability to scavenge host ATP. Nonetheless, ATP/AMP import is not mediated by TgPiT or TgPT2, suggesting additional mechanisms. Together, these results show the complex pathways of phosphate transport in Toxoplasma, and TgPT2 is a potential target for antitoxoplasmic intervention design due to its essential role in parasite growth.IMPORTANCE To grow and survive within host cells, Toxoplasma must scavenge necessary nutrients from hosts to support its parasitism. Transporters located in the plasma membrane of the parasites play critical roles in nutrient acquisition. Toxoplasma encodes a large number of transporters, but so far, only a few have been characterized. In this study, we identified two phosphate transporters, TgPiT and TgPT2, to localize to the plasma membrane of Toxoplasma. Although both TgPiT and TgPT2 possess phosphate transport activities, only the novel transporter TgPT2 was essential for parasite growth, both in vitro and in vivo. In addition, TgPT2 and its orthologs are only present in coccidia parasites. As such, TgPT2 represents a potential target for drug design against toxoplasmosis. In addition, our data indicated that Toxoplasma can take up ATP and AMP from the environment, providing new insights into the energy metabolism of Toxoplasma.

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part III: Helminths

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part III: Helminths

Understanding the Habitual Pattern of Concomitant Consumption of Herbs to Alleviate the Symptoms of Ulcerative Colitis by Comparative Proteome Analysis

Anchang decoction is an empirical prescription for the treatment of ulcerative colitis in China. In order to better understand its therapeutic function, large efforts have been made to identify its chemical constituents and to unravel the efficacy of its principal constituents. However, the molecular mechanism of its combinations is still unclear. Proteomics application has yielded some positive results in drug development and the identification of potential drug targets, suggesting the potential of this analytical approach to explore the action of molecular mechanisms of herbal formula by robustly addressing dynamic proteome changes. Label-free quantification and parallel reaction monitoring were used to identify differentially expressed proteins in the colon tissue of ulcerative colitis rats, fed with Anchang decoction and mesalazine, respectively. In this study, a total of 1,182 proteins were identified. From GO and KEGG analyses, the proteins of cytoskeleton and cytochrome P450 changed significantly with the occurrence of ulcerative colitis. In the meantime, antigen binding proteins and antioxidant-related proteins turned out to have drastic fluctuations with mesalazine and Anchang decoction. It has also been confirmed that KRT8, MYH11, FLNA, and LMNA are all related to the formation of ulcerative colitis based on parallel reaction monitoring analysis. The increase in FGG in the ulcerative colitis rat model is due to mesalazine, whereas that in KRT8 is due to Anchang decoction. The results from this study provide insights for the mechanism of action of Anchang decoction, which turns out to be an efficient technical pipeline for understanding worldwide medicinal herbs.

P1173: CLINICAL APPLICABILITY OF TARGETED NEXT-GENERATION SEQUENCING FOR PRECISION MEDICINE IN DIFFUSE LARGE B CELL LYMPHOMA

Background: The cure rate of diffuse large B-cell lymphoma is only 60-70%, and new treatment methods need to be found. Aims: Comprehensive genomic analysis based on next-generation sequencing (NGS) allows a better molecular characterization of diffuse large B-cell lymphoma, offering a roadmap toward precision medicine. Methods: We analyzed somatic alterations of 37 DLBCL tissue or blood samples by a hybridization capture-based NGS panel targeting 188 lymphoma-related genes. Results: Totally, 279 single-nucleotide variants and small insertions or deletions affecting 103 genes were identified, with at least 1 mutation detected in 100% (37/37) of cases. The most frequently mutated genes were those involved in epigenetic modifiers (DNMT3A, KMT2B and KMT2D), activated signaling (TYK2, MYD88, NOTCH2 and BCR) and transcription factors/transcriptional regulator (RUNX1, SPEN, IRF4, KLF2 and ASXL1). Significant co-occurrences were shown between RUNX1 mutations with NOTCH2, IRF4, ARID1A and BCR (P<0.05, respectively), BCR and IRF4 (P<0.01), etc. Additionally, we analyzed the association of genomic aberrations with clinicopathological features in DLBCL. Patients aged >60 years harbored less LRP1B mutations than those aged ≤60 years (5.3% vs. 33.3%, P< 0.05). The mutation frequency of TP53 was significantly higher in LDH-high (>244 U/L) group than that in LDH-low (≤244 U/L) group (40% vs. 6.25%, P<0.05). Compared with germinal center B-cell (GCB), the mutation frequency of TYK was significantly lower in non-GCB (5% vs. 36.4%, P<0.05). New potential therapeutic targets (CREBBP, EP300, EZH2, SMARCB1, CD79A/B, BTK, CARD11, MYD88, THFAIP3, PIK3CA, PTEN and JAK) were identified in 55% (11/20) of newly diagnosed patients and in 41.2% (7/17) of relapsed/refractory patients. Ibrutinib, as a single agent, has demonstrated limited activity in DLBCL with mutant MYD88 and wildtype CD79. In this study, we identified 3 patients with mutant MYD88 and wildtype CD79A/B (8.1%), among whom 2 harbored MYD88 L265P variants and 1 had MYD88 S219C mutation. Summary/Conclusion: The utility of mutational profiling may facilitate the identification of potential drug targets, which in turns may represent new therapeutic possibilities.

De Novo design of potential inhibitors against SARS-CoV-2 Mpro

The impact of the ravages of COVID-19 on people's lives is obvious, and the development of novel potential inhibitors against SARS-CoV-2 main protease (Mpro), which has been validated as a potential target for drug design, is urgently needed. This study developed a model named MproI-GEN, which can be used for the de novo design of potential Mpro inhibitors (MproIs) based on deep learning. The model was mainly composed of long-short term memory modules, and the last layer was re-trained with transfer learning. The validity (0.9248), novelty (0.9668), and uniqueness (0.0652) of the designed potential MproI library (PMproIL) were evaluated, and the results showed that MproI-GEN could be used to design structurally novel and reasonable molecules. Additionally, PMproIL was filtered based on machine learning models and molecular docking. After filtering, the potential MproIs were verified with molecular dynamics simulations to evaluate the binding stability levels of these MproIs and SARS-CoV-2 Mpro, thereby illustrating the inhibitory effects of the potential MproIs against Mpro. Two potential MproIs were proposed in this study. This study provides not only new possibilities for the development of COVID-19 drugs but also a complete pipeline for the discovery of novel lead compounds.

Clinical applicability of targeted next-generation sequencing for precision medicine in diffuse large B-cell lymphoma.

e19538 Background: Comprehensive genomic analysis based on next-generation sequencing (NGS) allows a better molecular characterization of diffuse large B-cell lymphoma (DLBCL), offering a roadmap toward precision medicine. Methods: We analyzed somatic alterations of 37 DLBCL tissue or blood samples by a hybridization capture-based NGS panel targeting 188 lymphoma-related genes. Results: Totally, 279 single-nucleotide variants and small insertions or deletions affecting 103 genes were identified, with at least 1 mutation detected in 100% (37/37) of cases. The most frequently mutated genes were those involved in epigenetic modifiers ( DNMT3A, KMT2B and KMT2D), activated signaling ( TYK2, MYD88, NOTCH2 and BCR) and transcription factors/transcriptional regulator ( RUNX1, SPEN, IRF4, KLF2 and ASXL1). Significant co-occurrences were shown between RUNX1 mutations with NOTCH2, IRF4, ARID1A and BCR ( P&lt; 0.05, respectively), BCR and IRF4 ( P&lt; 0.01), etc. Additionally, we analyzed the association of genomic aberrations with clinicopathological features in DLBCL. Patients aged &gt; 60 years harbored less LRP1B mutations than those aged ≤60 years (5.3% vs. 33.3%, P&lt; 0.05). The mutation frequency of TP53 was significantly higher in LDH-high (&gt; 244 U/L) group than that in LDH-low (≤244 U/L) group (40% vs. 6.25%, P&lt; 0.05). Compared with germinal center B-cell (GCB), the mutation frequency of TYK was significantly lower in non-GCB (5% vs. 36.4%, P&lt; 0.05). New potential therapeutic targets ( CREBBP, EP300, EZH2, SMARCB1, CD79A/B, BTK, CARD11, MYD88, THFAIP3, PIK3CA, PTEN and JAK) were identified in 55% (11/20) of newly diagnosed patients and in 41.2% (7/17) of relapsed/refractory patients. Ibrutinib, as a single agent, has demonstrated limited activity in DLBCL with mutant MYD88 and wildtype CD79. In this study, we identified 3 patients with mutant MYD88 and wildtype CD79A/B (8.1%), among whom 2 harbored MYD88 L265P variants and 1 had MYD88 S219C mutation. Conclusions: The utility of mutational profiling may facilitate the identification of potential drug targets, which in turns may represent new therapeutic possibilities.

In silico Structural and Functional Characterization of a Hypothetical Protein from Stenotrophomonas maltophilia SRM01

Stenotrophomonas maltophilia is a low-virulence opportunistic pathogen that causes human infections, especially in profound ill patients. Even if the bacterial genomes seem understood, the activities of many proteins are unknown. The purpose of our current research is to unravel the functional characteristics i.e. functional domain search and valuable regions of a hypothetical protein that would aid in the identification of potential drug targets in Stenotrophomonas maltophilia. The hypothetical protein of S.maltophilia was located and annotated using different in silico techniques. Our target protein was predicted to be Transcrip Reg superfamily YebC/PmpR based on motif and domain analysis by functional annotation tools. The regulator proteins of the YebC family are part of a vast collection of widely conserved hypothetical proteins with unclear functions. Examining and reviewing the function of YebC family protein, they repress Quorum sensing by directly binding to the promoter region of QS master regulator pqrS. It has also been reported that T3SS expression is regulated by YebC, to activate the virulence expression direct interaction with one of the T3SS promoters is needed.

Research Status of the Orphan G Protein Coupled Receptor 158 and Future Perspectives.

G-protein-coupled receptors (GPCRs) remain one of the most successful targets for therapeutic drugs approved by the US Food and Drug Administration (FDA). Many novel orphan GPCRs have been identified by human genome sequencing and considered as putative targets for refractory diseases. Of note, a series of studies have been carried out involving GPCR 158 (or GPR158) since its identification in 2005, predominantly focusing on the characterization of its roles in the progression of cancer and mental illness. However, advances towards an in-depth understanding of the biological mechanism(s) involved for clinical application of GPR158 are lacking. In this paper, we clarify the origin of the GPR158 evolution in different species and summarize the relationship between GPR158 and different diseases towards potential drug target identification, through an analysis of the sequences and substructures of GPR158. Further, we discuss how recent studies set about unraveling the fundamental features and principles, followed by future perspectives and thoughts, which may lead to prospective therapies involving GPR158.

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part II: Parasite targets

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part II: Parasite targets

The Roles of Transient Receptor Potential Ion Channels in Pathologies of Glaucoma.

Transient receptor ion potential (TRP) channels are a cluster of non-selective cation channels present on cell membranes. They are important mediators of sensory signals to regulate cellular functions and signaling pathways. Alterations and dysfunction of these channels could disrupt physiological processes, thus leading to a broad array of disorders, such as cardiovascular, renal and nervous system diseases. These effects position them as potential targets for drug design and treatment. Because TRP channels can mediate processes such as mechanical conduction, osmotic pressure, and oxidative stress, they have been studied in the context of glaucoma. Glaucoma is an irreversible blinding eye disease caused by an intermittent or sustained increase in intraocular pressure (IOP), which results in the apoptosis of retinal ganglion cells (RGCs), optic nerve atrophy and eventually visual field defects. An increasing number of studies have documented that various TRP subfamilies are abundantly expressed in ocular structures, including the cornea, lens, ciliary body (CB), trabecular meshwork (TM) and retina. In alignment with these findings, there is also mounting evidence supporting the potential role of the TRP family in glaucoma progression. Therefore, it is of great interest and clinical significance to gain an increased understanding of these channels, which in turn could shed more light on the identification of new therapeutic targets for glaucoma. Moreover, this role is not understood completely to date, and whether the activation of TRP channels contributes to glaucoma, or instead aggravates progression, needs to be explored. In this manuscript, we aim to provide a comprehensive overview of recent research on TRP channels in glaucoma and to suggest novel targets for future therapeutic interventions in glaucoma.

A Comparative Computational Analysis Approach to Predict Significant Protein-Protein Interactions of Human and Vancomycin Resistant Enterococcus faecalis (VRE) to Prioritize Potential Drug Targets

Background: Various challenges exist in the treatment of infectious diseases due to the significant rise in drug resistance, resulting in the failure of antibiotic treatment. As a consequence, a dire need has arisen for the rethinking of the drug discovery cycle because of the challenge of drug resistance. The underlying cause of the infectious diseases depends upon associations within the Host-pathogen Protein- Protein Interactions (HP-PPIs) network, which represents a key to unlock new pathogenesis mechanisms. Hence, the elucidation of significant PPIs is a promising approach for the identification of potential drug targets. Objective: Identification of the most significant HP-PPIs and their partners, and targeting them to prioritize potential new drug targets against Vancomycin-resistant Enterococcus faecalis (VRE). Methods: We applied a computational approach based on one of the emerging techniques i.e. Interolog methodology to predict the significant Host-Pathogen PPIs. Structure-Based Studies were applied to model shortlisted protein structures and validate them through PSIPRED, PROCHECK, VERIFY3D, and ERRAT tools. Furthermore, 18,000 drug-like compounds from the ZINC library were docked against these proteins to study protein-chemical interactions using the AutoDock based molecular docking method. Results: The study resulted in the identification of 118 PPIs for Enterococcus faecalis, and prioritized two novel drug targets i.e. Exodeoxyribonuclease (ExoA) and ATP-dependent Clp protease proteolytic subunit (ClpP). Consequently, the docking program ranked 2,670 and 3,154 compounds as potential binders against Exodeoxyribonuclease and ATP-dependent Clp protease proteolytic subunit, respectively. Conclusion: Thereby, the current study enabled us to identify and prioritize potential PPIs in VRE and their interacting proteins in human hosts along with the pool of novel drug candidates.

TRIM26-mediated degradation of nucleocapsid protein limits porcine reproductive and respiratory syndrome virus-2 infection

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, has ranked among the most economically important veterinary infectious diseases globally. Recently, tripartite motif (TRIMs) family members have arisen as novel restriction factors in antiviral immunity. Noteworthy, TRIM26 was reported as a binding partner of IRF3, TBK1, TAB1, and NEMO, yet its role in virus infection remains controversial. Herein, we showed that TRIM26 bound N protein by the C-terminal PRY/SPRY domain. Moreover, ectopic expression of TRIM26 impaired PRRSV replication and induced degradation of N protein. The anti-PRRSV activity was independent of the nuclear localization signal (NLS). Instead, deletion of the RING domain, or the PRY/SPRY portion, abrogated the antiviral function. Finally, siRNA depletion of TRIM26 resulted in enhanced production of viral RNA and virus yield in porcine alveolar macrophages (PAMs) after PRRSV infection. Overexpression of an RNAi-resistant TRIM26 rescue-plasmid led to the acquisition of PRRSV restriction in TRIM26-knockdown cells. Together, these data add TRIM26 as a potential target for drug design against PRRSV.

The applications of deep learning algorithms on in silico druggable proteins identification

IntroductionThe top priority in drug development is to identify novel and effective drug targets. In vitro assays are frequently used for this purpose; however, traditional experimental approaches are insufficient for large-scale exploration of novel drug targets, as they are expensive, time-consuming and laborious. Therefore, computational methods have emerged in recent decades as an alternative to aid experimental drug discovery studies by developing sophisticated predictive models to estimate unknown drugs/compounds and their targets. The recent success of deep learning (DL) techniques in machine learning and artificial intelligence has further attracted a great deal of attention in the biomedicine field, including computational drug discovery. ObjectivesThis study focuses on the practical applications of deep learning algorithms for predicting druggable proteins and proposes a powerful predictor for fast and accurate identification of potential drug targets. MethodsUsing a gold-standard dataset, we explored several typical protein features and different deep learning algorithms and evaluated their performance in a comprehensive way. We provide an overview of the entire experimental process, including protein features and descriptors, neural network architectures, libraries and toolkits for deep learning modelling, performance evaluation metrics, model interpretation and visualization. ResultsExperimental results show that the hybrid model (architecture: CNN-RNN (BiLSTM) + DNN; feature: dictionary encoding + DC_TC_CTD) performed better than the other models on the benchmark dataset. This hybrid model was able to achieve 90.0% accuracy and 0.800 MCC on the test dataset and 84.8% and 0.703 on a nonredundant independent test dataset, which is comparable to those of existing methods. ConclusionWe developed the first deep learning-based classifier for fast and accurate identification of potential druggable proteins. We hope that this study will be helpful for future researchers who would like to use deep learning techniques to develop relevant predictive models.

Subtractive proteomic analysis for identification of potential drug targets and vaccine candidates against Burkholderia pseudomallei K96243

Burkholderia pseudomallei is regarded as a global threat because of its ability to cause melioidosis, and potential as bioweapon. Intrinsic resistance to frontline antibiotics remains a major challenge in treating melioidosis. The increasing global burden of B. pseudomallei triggers the need to develop effective drugs and vaccine for controlling this pathogen. Therefore, we analyzed the whole proteome of B. pseudomallei K96243 using subtractive proteomic and immune-informatic analysis to find out potential drug target and vaccine candidate. Our analysis revealed 45 essential and non-homologous metabolic proteins, involved in different unique metabolic pathways. 36 out of 45 proteins can serve as novel drug targets and the remaining proteins had already been targeted with experimental drugs. 2 novel targets of cytoplasmic localization, namely dihydroneopterin aldolase and phosphoribosyl transferase were subjected to molecular docking with 14 antibiotics, which revealed the strong binding affinity of cefiderocol and tetracycline to the identified targets. Moreover, 100 ns molecular dynamic simulation and MM-PBSA calculation revealed the stability of drug-protein complexes. On the contrary, highly antigenic, non-allergic and non-toxic epitopes from three essential outer membrane proteins were joined by linkers and adjuvant to construct a chimeric peptide vaccine. The vaccine construct could efficiently bind to TLR-4 and generated robust immune response. The vaccine-receptor complex showed minimum deformability and good stability. Overall, our findings will aid in designing new inhibitors that disrupts the functionality of proposed targets and in the development of subunit vaccine for the therapeutic and prophylactic management of B. pseudomallei.

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part I: Drug resistance

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part I: Drug resistance

Assessment of intercontinents mutation hotspots and conserved domains within SARS-CoV-2 genome.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 pathogen, has led to waves of global pandemic claiming lives and posing a serious threat to public health and social cum physical interactions. To evaluate the mutational landscape and conserved regions in the genome of the causative pathogen, we analysed 7213 complete SARS-CoV-2 protein sequences mined from the Global Initiative on Sharing All Influenza Data (GISAID) repository from infected patients across all regions on the EpiCov web interface. Regions of origin and the corresponding number of sequences mined are as follows: Asia – 2487; Oceania – 2027; Europe – 1240; Africa – 717; South America – 391; and North America – 351. High recurrent mutations, namely: T265I in non-structural protein 2 (nsp2), L3606F in nsp6, P4715L in RNA-dependent RNA polymerase (RdRp), D614G in spike glycoprotein, R203K and G204R in nucleocapsid phosphoprotein and Q57H in ORF3a with well-conserved envelope and membrane proteins, 3CLpro and spike S2 domains across regions were observed. Comparative analyses of the viral sequences reveal the prevalence P4715L and D614G mutations as the most recurrent and concurrent in Africa (97.20%), Europe (89.83%) and moderately in Asia (61.60%). Mutation rates are central to viral transmissibility, evolution and virulence, which help them to invade host immunity and develop drug resistance. Based on the foregoing, it is important to understand the mutational spectra of SARS-CoV-2 genome across regions. This will help in identifying specific genomic sites as potential targets for drug design and vaccine development, monitoring the spread of the virus and unraveling its evolution, virulence and transmissibility.

Identification of Potential Drug Targets of Broad-Spectrum Inhibitors with a Michael Acceptor Moiety Using Shotgun Proteomics.

The Michael addition reaction is a spontaneous and quick chemical reaction that is widely applied in various fields. This reaction is performed by conjugating an addition of nucleophiles with α, β-unsaturated carbonyl compounds, resulting in the bond formation of C-N, C-S, C-O, and so on. In the development of molecular materials, the Michael addition is not only used to synthesize chemical compounds but is also involved in the mechanism of drug action. Several covalent drugs that bond via Michael addition are regarded as anticarcinogens and anti-inflammatory drugs. Although drug development is mainly focused on pharmaceutical drug discovery, target-based discovery can provide a different perspective for drug usage. However, considerable time and labor are required to define a molecular target through molecular biological experiments. In this review, we systematically examine the chemical structures of current FDA-approved antiviral drugs for potential Michael addition moieties with α, β-unsaturated carbonyl groups, which may exert an unidentified broad-spectrum inhibitory mechanism to target viral or host factors. We thus propose that profiling the targets of antiviral agents, such as Michael addition products, can be achieved by employing a high-throughput LC-MS approach to comprehensively analyze the interaction between drugs and targets, and the subsequent drug responses in the cellular environment to facilitate drug repurposing and/or identify potential adverse effects, with a particular emphasis on the pros and cons of this shotgun proteomic approach.

Phytoconstituents and Medicinal Plants for Anticancer Drug Discovery: Computational Identification of Potent Inhibitors of PIM1 Kinase.

Natural products, medicinal plants, and phytoconstituents serve as important sources and accelerators for anticancer drug discovery, especially when they are combined with virtual screening and molecular simulations against molecular drug targets. Proto-oncogene serine/threonine-protein kinase Pim1 (PIM1) is involved in cell survival and proliferation, with great relevance for oncogenesis. PIM1 plays a major role in the progression of various common complex human cancers, including prostate cancer, acute myeloid leukemia, and other hematopoietic malignancies. The overexpression of PIM1 leads to cancer progression, and thus it is considered as a potential target for drug design and development purposes. Here, we report original in silico findings by employing structure-based virtual screening to discover potential phytoconstituents from the medicinal plants-based compounds, which could inhibit the PIM1 activity, using the IMPPAT (a curated database of Indian Medicinal Plants, Phytochemistry And Therapeutics) database. The initial hits were selected based on their binding affinity toward PIM1 calculated through the molecular docking approach. Subsequently, interaction analyses and molecular dynamics (MD) simulation for 100 ns was carried out to study the conformational dynamics and complex stability of PIM1 with the identified compounds. Importantly, we found that PIM1 forms stable protein-ligand complexes with the phytoconstituents Dehydrotectol and Nordracorubin in particular. Our findings suggest that identified phytoconstituents Dehydrotectol and Nordracorubin bind to PIM1 in ATP-competitive binding mode. These findings and the compounds reported herein warrant further exploration as promising scaffolds for anticancer drug design, discovery, and development.

ALTERATIONS OF ALDOSE REDUCTASE ACTIVITY BY INDOLE-3-CARBOXALDEHYDE DERIVATIVES

In diabetic conditions, aldose reductase (AR, EC 1.1.1.21) activity is significantly increased in lens, kidney and nerve tissues. Mainly in ocular and neural tissues increased levels of sorbitol is associated with diabetic complications such as retinopathy, nephropathy, neuropahty, cataract formation and also tissue damage via increased reactive oxygen speices. Recently, there are many studies that show the relationship between this enzyme family and cancer. Aldose reductase is important for the pathway and in turn has been a potential target for drug design. Great number of aldose reductase inhibitors (ARIs) are used for prevention or delay of these diabetic complications and cancer. However, effective ARIs which has benefits in diabetic complications are still under investigation. In this study aldose reductase was partially purified from bovine lens and the inhibitory effects of 16 different indol-3-carboxyaldehydederivatives on aldose reductase enzyme activities were examined by kinetic assays. These results suggested that N'-[(5-bromo-1H-indol-3-yl)methylidene]pyridine-4-carbohydrazide showed that the highest inhibitory activity on AR.