Drug Target Molecules Research Articles

Exploring Antimicrobial Potency, ADMET, and Optimal Drug Target of a Non-ribosomal Peptide Sevadicin from Bacillus pumilus, through In Vitro Assay and Molecular Dynamics Simulation.

The current study was designed to explore the biosynthetic potential of sevadicin in Bacillus pumilus species and its interaction with bacterial drug target molecules. The non-ribosomal peptide (NRP) cluster in B. pumilus SF-4 was preliminarily confirmed using PCR-based screening, and the bioactivity of strain SF-4 culture extract was assessed against a set of human pathogenic strains. The susceptibility assay showed that strain SF-4 extract had higher inhibitory concentrations (312-375µg/mL) than ciprofloxacin. Genome mining of B. pumilus strains (n = 22) using AntiSMASH and BAGEL identified sevadicin coding biosynthetic gene cluster only in strain SF-4, constitutes of two core biosynthetic genes, three additional biosynthetic genes, two transport-related genes, and one regulatory gene. The molecular docking of sevadicin with various putative bacterial drug targets such as dihydropteroate, muramyl ligase E, topoisomerase, penicillin-binding protein, and in vitro safety analyses were conducted with detailed ADMET screening. The results showed that sevadicin makes hydrophobic interaction with MurE (PDB ID: 1E8C and 4C13) via hydrogen bonding, suggesting bacterial growth inhibition by disrupting the cell wall synthesis pathway and exhibiting a secure biosafety profile. The stability and compactness of sevadicin/MurE complexes were assessed via molecular dynamic simulation using RMSD, RMSF, and Rg. The simulation results revealed the binding stability of sevadicin/MurE complexes and indicated that the complexes can't be easily deformed. In conclusion, the current study explored the biosynthesis of sevadicin in B. pumilus for the first time and found that sevadicin inhibits bacterial growth by inhibiting cell wall synthesis via targeting the MurE enzyme and exhibits no toxicity.

Computer-Aided Drug Design Using the Fragment Molecular Orbital Method: Current Status and Future Applications for SBDD.

Owing to the increasing use of computers, computer-aided drug design (CADD) has become an essential component of drug discovery research. In structure-based drug design (SBDD), including inhibitor design and in silico screening of drug target molecules, concordance with wet experimental data is important to provide insights on unique perspectives derived from calculations. Fragment molecular orbital (FMO) method is a quantum chemical method that facilitates precise energy calculations. Fragmentation method makes it possible to apply the quantum chemical method to biological macromolecules for energy calculation based on the electron behavior. Furthermore, interaction energies calculated on a residue-by-residue basis via fragmentation aid in the analysis of interactions between the target and ligand molecule residues and molecular design. In this review, we outline the recent developments in SBDD and FMO methods and highlight the prospects of developing machine learning approaches for large computational data using the FMO method.

Exploring the potential molecular intersection of stroke and major depression disorder

Stroke and major depression disorder are common neurological diseases, and a large number of clinical studies have shown that there is a close relationship between the two diseases, but whether the two diseases are linked at the genetic level needs to be further explored. The purpose of this study was to explore the comorbidity mechanism of stroke and major depression by using bioinformatics technology and animal experiments. From the GEO database, we gathered transcriptome data of stroke and depression mice (GSE104036, GSE131712, GSE81672, and GSE146845) and identified comorbid gene set through edgR and WGCNA analyses. Further analysis revealed that these genes were enriched in pathways associated with cell death. Programmed cell death gene sets (PCDGs) are generated from genes related to apoptosis, necroptosis, pyroptosis and autophagy. The intersection of PCDGs and comorbid gene set resulted in two hub genes, Mlkl and Nlrp3. Single-cell sequencing analysis indicated that Mlkl and Nlrp3 are mainly influential on endothelial cells and microglia, suggesting that the impairment of these two cell types may be a factor in the relationship between stroke and major depression. This was experimentally confirmed by RT–PCR and immunofluorescence staining. Our research revealed that two specific genes, namely, Mlkl and Nlrp3, play crucial roles in the complex mechanism that links stroke and major depression. Additionally, we have predicted six possible therapeutic agents and the outcomes of docking simulations of target proteins and drug molecules.

Exploring avenues for Alzheimer’s drugs: current status and future outlook

Alzheimer’s disease (AD) is a progressive neurological disease that causes cognitive impairment in old aged persons. It is the cause of a wide spectrum of neurodegenerative disturbances including tauopathies, which are responsible for progressive neuronal degeneration and impaired cognitive functions. Although drug discovery researchers and pharmaceutical companies are meticulously working to develop novel drugs for AD, establishing their safety and efficacy proofs are major challenges for them. In this review, we have discussed about AD and its causes mainly focusing on molecular targets with their physiological and pathophysiological roles, therapeutic approaches, and their future perspectives. We have compiled the information about novel and promising drug targets and lead data bases that will help to select appropriate target and design novel drug molecules for the treatment of Alzheimer.

Analysis of comprehensive biomolecules in critically ill patients via bioinformatics technologies.

Each patient with a critical illness such as sepsis and severe trauma has a different genetic background, comorbidities, age, and sex. Moreover, pathophysiology changes dynamically over time even in the same patient. Therefore, individualized treatment is necessary to account for heterogeneity in patient backgrounds. Recently, the analysis of comprehensive biomolecular information using clinical specimens has revealed novel molecular pathological classifications called subtypes. In addition, comprehensive biomolecular information using clinical specimens has enabled reverse translational research, which is a data-driven approach to the identification of drug target molecules. The development of these methods is expected to visualize the heterogeneity of patient backgrounds and lead to personalized therapy.

Deciphering the chemical constituents and antimicrobial activity of Prangos pabularia Lindl. using LC-MS/MS in combination with experimental evaluation and computational studies

This study meticulously explores the antimicrobial potential of Prangos pabularia Lindl.’s aerial parts through a comprehensive blend of in vitro and in silico analysis. Extracts with varying polarities underwent LC-MS/MS identification of active components, followed by in vitro and in silico assessments of antimicrobial efficacy against Escherichia coli, Bacillus cereus, Candida albicans, Candida glabrata, and Candida paropsilosis. The methanolic extract exhibited significant antimicrobial activity with a MIC value of 48 μg/mL against all tested strains. Molecular docking revealed the compound 9-(3-methylbut-2-enoxy)-furo-(3,2-g)-chromen-7-one’s highest binding affinity against the penicillin-binding protein (PBP) bacterial drug target molecule. Other compounds also displayed substantial interactions with key antimicrobial drug target proteins. Further, Molecular dynamics simulations affirmed the stability of protein and ligand conformations. Collectively, these results underscore Prangos pabularia Lindl.’s aerial parts as a promising botanical resource in combating diverse microbial infections. This comprehensive approach not only validates it’s in vitro antimicrobial properties but also provides molecular insights into interaction mechanisms, advancing our comprehension of the plant’s therapeutic potential.

Development of a vaccine against the synthetic opioid U-47700.

Opioid use disorders and overdose have become a major public health concern in recent years. U-47700, a New psychoactive substances (NPS) opioid, also known as "pinky" or "pink" has been identified as a new threat in the drug supply because of its potency and abuse potential. Conjugate vaccines that can produce antibodies against target drug molecules have emerged as a promising tool to treat substance use disorders. Herein, we report the design, synthesis, and in vivo characterization of a U-47700 vaccine. The vaccine demonstrated favorable results with rodents producing elevated levels of antibody titer and sub-micromolar affinity to U-47700. In addition, antibodies generated by the vaccine effectively mitigated drug-induced effects by preventing the drug from penetrating the blood-brain barrier, which was verified by antinociception and drug biodistribution studies. The development of a vaccine against U-47700 and other NPS opioids contributes to the continued advancement of non-conventional pharmacological treatments to address the global opioid epidemic.

HER 2 Targeted Therapy and Its Potential Risk of Drug Resistance

HER2, human epidermal receptor 2(c-erbB-2 gene), is a hot targeted point in various cancers targeted therapy. Breast cancer including HER2 positive or negative. HER2 is an oncogenic receptor tyrosine kinase. HER2 gene amplification occurs in some of breast cancers (BCS), resulting in overexpression of the HER2 protein. Compared to the trastuzumab or pertuzumab, the performance of trastuzumab deruxtecan is excellent. Drug resistance is known to be the main cause of failure of tumor chemotherapy. Tumor drug resistance involves various mechanisms, such as those involving decreased intracellular drug concentration, changes of drug target molecules, metabolic detoxification, and imbalance of DNA damage repair function. HER2-positive breast cancer becomes resistant to trastuzumab, thereby blocking effective binding and developing resistance. The significance of this review is to understand the mechanism of drug resistance from molecular and chemotherapy perspectives by studying the structure and overexpression of HER2 protein as predictors, so as to grasp the progress of current targeted drug therapy. Our review starting from HER2 and its targeted therapy gets to the deep insight into the antibody drug conjugates and explores the possible proteins which may become the potential targeted points in future research.

Microsecond-long simulation reveals the molecular mechanism for the dual inhibition of falcipain-2 and falcipain-3 by antimalarial lead compounds.

The latest world malaria report revealed that human deaths caused by malaria are currently on the rise and presently stood at over 627,000 per year. In addition, more than 240 million people have the infection at any given time. These figures make malaria the topmost infectious disease and reiterate the need for continuous efforts for the development of novel chemotherapies. Malaria is an infectious disease caused majorly by the protozoan intracellular parasite Plasmodium falciparum and transmitted by mosquitoes. Reports abound on the central role of falcipains (cysteine protease enzymes) in the catabolism of hemoglobin for furnishing the plasmodium cells with amino acids that they require for development and survival in the hosts. Even though falcipains (FPs) have been validated as drug target molecules for the development of new antimalarial drugs, none of its inhibitory compounds have advanced beyond the early discovery stage. Therefore, there are renewed efforts to expand the collection of falcipain inhibitors. As a result, an interesting finding reported the discovery of a quinolinyl oxamide derivative (QOD) and an indole carboxamide derivative (ICD), with each compound demonstrating good potencies against the two essential FP subtypes 2 (FP-2) and 3 (FP-3). In this study, we utilized microsecond-scale molecular dynamics simulation computational method to investigate the interactions between FP-2 and FP-3 with the quinolinyl oxamide derivative and indole carboxamide derivative. The results revealed that quinolinyl oxamide derivative and indole carboxamide derivative bound tightly at the active site of both enzymes. Interestingly, despite belonging to different chemical scaffolds, they are coordinated by almost identical amino acid residues via extensive hydrogen bond interactions in both FP-2 and FP-3. Our report provided molecular insights into the interactions between FP-2 and FP-3 with quinolinyl oxamide derivative and indole carboxamide derivative, which we hope will pave the way towards the design of more potent and druglike inhibitors of these enzymes and will pave the way for their development to new antimalarial drugs.

S10.4a New mechanism and detection methods for azole-resistant Aspergillus fumigatus

S10.4 Emerging antifungal resistant fungi, September 24, 2022, 10:30 AM - 12:00 PMThe most studied azole-resistant mechanism of Aspergillus fumigatus is decreased affinity of the drug for CYP51A, the drug target molecule, due to its amino acid substitutions. Typically, each azole-resistance caused by the designated amino acid substitution of CYP51A has a specific pattern depending on the substitution site. While uncovering non-cyp51A mechanisms responsible for azole resistance should be essential for developing novel methods for prompt diagnosis and effective drug treatment. In our previous study, we reported results that mutation of hmg1, which codes HMG-CoA reductase, the rate-limiting enzyme in ergosterol biosynthesis, would be the mechanism conferring azole-drugs resistance (EID 2018). On the other hand, different azole susceptibility patterns have been reported even among the strains possessing the same mutation in CYP51A. In this way, the overall picture of molecular mechanisms inducing azole resistance remains unclear. We performed a comparative genomic analysis among the strains with the same cyp51A mutation isolated from the same patient but with different azole resistance patterns. To investigate the association between the novel mutation and azole resistance, the mutant allele was replaced with the wild-type allele by the CRISPR-Cas9 system. Antifungal susceptibility tests were performed according to the CLSI-M38. As a result of genome comparison analysis between these two strains using the HiSeq sequencing system (Illumina), another mutation was found in the insulin-induced protein (INSIG) of the multiazole-resistant strain. The INSIG mutation contributes additively to azole resistance in collaboration with the CYP51A mutation but does not alone itself. We have already reported simple and rapid detection methods for A. fumigatus possessing CYP51A mutation using an endonuclease (AAC 2020). Furthermore, using MALDI-TOF-MS, we are developing a discriminant model to detect azole-resistant A. fumigatus.

AMPKα2/HNF4A/BORIS/GLUT4 pathway promotes hepatocellular carcinoma cell invasion and metastasis in low glucose microenviroment

Increasing evidence has revealed that the invasion and metastasis of HCC are intimately related to the low-glucose microenvironment, but the intrinsic regulatory mechanism remains unclear. It has been well documented that AMPK regulates the transcriptional expression of GLUT4 and its catalytic subunit AMPKα2 can negatively regulate the downstream target molecule HNF4A. Meanwhile, BORIS (Brother of the Regulator of Imprinted Sites) is able to modulate the Warburg effect by regulating the splicing of pyruvate kinase M2 (PKM2), a critical enzyme in glycolysis. Through bioinformatic analysis and a series of overexpression, knockdown, and complementation experiments, we demonstrated that HNF4A can directly act on BORIS and negatively regulate its expression, thereby inhibiting hepatoma cell motility and tumor metastasis, whereas BORIS can directly act on GLUT4 and positively regulate its expression to enhance hepatoma cell motility and tumor metastasis. We also found that HNF4A agonist (Benfluorex) and GLUT4 inhibitor (antiviral drug Ritonavir) can suppress HCC cell proliferation and glucose uptake. Taken together, these results all suggest that activation of the AMPKα2/HNF4A/BORIS/GLUT4 signaling pathway in a low-glucose microenvironment can significantly promote the invasion and metastasis of HCC cells, while HNF4A and GLUT4 may have important potential applications as prognostic or drug target molecules.

A secreted MIF homologue from Trichinella spiralis binds to and interacts with host monocytes

Trichinella spiralis is a very successful parasite capable of surviving in many mammal hosts and residing in muscle tissues for long periods, indicating that it must have some effective strategies to escape from or guard against the host immune attack. The functions of MIF have been studied in other parasites and demonstrated to function as a virulence factor aiding in their survival by modulating the host immune response. However, the functions of Trichinella spiralis MIF (TsMIF) have not been addressed. Here, we successfully obtained the purified recombinant TsMIF and anti-TsMIF serum. Our results showed that TsMIF was expressed in all the Trichinella spiralis developmental stages, especially highly expressed in the muscle larvae (ML) and mainly located in stichocytes, midgut, cuticle, muscle cells of ML and around intrauterine embryos of female adults. We also observed TsMIF could be secreted from ML and bind to host monocytes. Next, our data demonstrated that TsMIF not only stimulated the phosphorylation of ERK1/2 and cell proliferation by binding to the host cell surface receptor CD74, but also interacted with a host intracellular protein, Jab1, which is a coactivator of AP-1 transcription. We concluded the secreted TsMIF plays an important role in the interaction between Trichinella spiralis and its host and could be a potential drug or vaccine target molecule against Trichinella spiralis infection.

Identification of a novel target site for ATP-independent ERK2 inhibitors

Extracellular signal-regulated kinase 2 (ERK2) controls vital physiological processes involving proliferation and differentiation and is a drug target molecule for many diseases such as cancers. In silico screening focusing on an allosteric site that plays a crucial role in substrate anchoring conferred an ERK2 inhibitor (compound 1). However, a competitive binding assay indicated that compound 1 did not bind to the allosteric site. Here, the crystal structure of ERK2 in complex with compound 1 revealed a novel binding site. This finding demonstrates the feasibility of developing new types of ERK2 inhibitors.

Identification of SARS-CoV-2 main protease inhibitors from FDA-approved drugs by artificial intelligence-supported activity prediction system

Although a certain level of efficacy and safety of several vaccine products against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been established, unmet medical needs for orally active small molecule therapeutic drugs are still very high. As a key drug target molecule, SARS-CoV-2 main protease (Mpro) is focused and large number of in-silico screenings, a part of which were supported by artificial intelligence (AI), have been conducted to identify Mpro inhibitors both through drug repurposing and drug discovery approaches. In the many drug-repurposing studies, docking simulation-based technologies have been mainly employed and contributed to the identification of several Mpro binders. On the other hand, because AI-guided INTerprotein’s Engine for New Drug Design (AI-guided INTENDD), an AI-supported activity prediction system for small molecules, enables to propose the potential binders by proprietary AI scores but not docking scores, it was expected to identify novel potential Mpro binders from FDA-approved drugs. As a result, we selected 20 potential Mpro binders using AI-guided INTENDD, of which 13 drugs showed Mpro-binding signal by surface plasmon resonance (SPR) method. Six (6) compounds among the 13 positive drugs were identified for the first time by the present study. Furthermore, it was verified that vorapaxar bound to Mpro with a Kd value of 27 µM by SPR method and inhibited virus replication in SARS-CoV-2 infected cells with an EC50 value of 11 µM. Communicated by Ramaswamy H. Sarma

Targeting novel coronavirus SARS-CoV-2 spike protein with phytoconstituents of Momordica charantia

BackgroundInfections by the SARS-CoV-2 virus causing COVID-19 are presently a global emergency. The current vaccination effort may reduce the infection rate, but strain variants are emerging under selection pressure. Thus, there is an urgent need to find drugs that treat COVID-19 and save human lives. Hence, in this study, we identified phytoconstituents of an edible vegetable, Bitter melon (Momordica charantia), that affect the SARS-CoV-2 spike protein.MethodsComponents of Momordica charantia were tested to identify the compounds that bind to the SARS-CoV-2 spike protein. An MTiOpenScreen web-server was used to perform docking studies. The Lipinski rule was utilized to evaluate potential interactions between the drug and other target molecules. PyMol and Schrodinger software were used to identify the hydrophilic and hydrophobic interactions. Surface plasmon resonance (SPR) was employed to assess the interaction between an extract component (erythrodiol) and the spike protein.ResultsOur in-silico evaluations showed that phytoconstituents of Momordica charantia have a low binding energy range, -5.82 to -5.97 kcal/mol. A docking study revealed two sets of phytoconstituents that bind at the S1 and S2 domains of SARS-CoV-2. SPR showed that erythrodiol has a strong binding affinity (KD = 1.15 μM) with the S2 spike protein of SARS-CoV-2. Overall, docking, ADME properties, and SPR displayed strong interactions between phytoconstituents and the active site of the SARS-CoV-2 spike protein.ConclusionThis study reveals that phytoconstituents from bitter melon are potential agents to treat SARS-CoV-2 viral infections due to their binding to spike proteins S1 and S2.

STEPS IN THE PROCESS OF NEW DRUG DEVELOPMENT

This review determines the various stages of drug discovery, pre clinical trials and clinical trials. This process involves the identification of chemical compound, synthesis, characterization, validation, optimization, screening and assay for therapeutic efficacy. Once a new drug target or promising molecule has been identified the process of moving from the science laboratory to the pre clinical to clinical trials have been discussed in this article. The main aim of this process is identifying the chemical compound which is therapeutically useful in treating and curing the disease. The most common steps in the development of a new drug are discovery or synthesis of a potential new drug compound or elucidation of a new drug. Once a chemical compound has shown its therapeutic efficacy in these investigations, it will initiate the process of drug development earlier to clinical trials. The drug development from initial idea to the market is a very complex process which can take upto 5 to 10 years and cost of $17 billion. Due to high budget of research & development and clinical trials drug discovery process is the most expensive. The average time taken for the drug discovery is almost 12 -15 years to develop a single new compound and enter into market

Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease.

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD), characterized by chronic inflammation and accumulation of fat in liver tissue. Affecting estimated 35 million people globally, NASH is the most common chronic liver condition in Western populations, and with patient numbers growing rapidly, the market for NASH therapy is projected to rise to $27.2 B in 2029. Despite this clinical need and attractive commercial opportunity, there are no Food and Drug Administration (FDA)-approved therapies specifically for this disease. Many have tried and unfortunately failed to find a drug, or drug combination, capable of unravelling the complexities of this metabolic condition. At the time of writing this review, only Zydus Cadila’s new drug application for Saroglitazar had been approved (2020) for NASH therapy in India. However, it is hoped that this dearth of therapy options will improve as several drug candidates progress through late-stage clinical development. Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Pharmaceuticals), Resmetirom (Madrigal Pharmaceuticals), Dapagliflozin and Semaglutide (Novo Nordisk) are in advanced Phase 3 clinical trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Therapeutics), Lanifibranor (Inventiva), Efruxifermin (Akero) and Tesamorelin (Theratechnologies) are expected to start Phase 3 trials soon. Here, we have performed an exhaustive review of the current therapeutic landscape for this disease and compared, in some detail, the fortunes of different drug classes (biologics vs small molecules) and target molecules. Given the complex pathophysiology of NASH, the use of drug combination, different mechanisms of actions and the targeting of each stage of the disease will likely be required. Hence, the development of a single therapy for NASH seems challenging and unlikely, despite the plethora of later stage trials due to report. We therefore predict that clinical, patient and company interest in pipeline and next-generation therapies will remain high for some time to come.

Inflammatory pathways in pathological neovascularization in retina and choroid: a narrative review on the inflammatory drug target molecules in retinal and choroidal neovascularization

Inflammatory pathways in pathological neovascularization in retina and choroid: a narrative review on the inflammatory drug target molecules in retinal and choroidal neovascularization

In silico Studies of Novel Synthetic Compounds as Potential Drugs to Inhibit Coronavirus (SARS-CoV-2): A Systematic Review

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), detected first in China, spread out fast to other parts of the world, and was soon recognized as a pandemic in March 2020. According to WHO, 179.686.071 confirmed cases and 3.899.172 deaths due to new coronavirus were reported worldwide on 26th June 2021. Despite countless efforts in searching for repositioned drugs to treat this disease, the results are still modest. Thus, the search for new molecular entities in the treatment of COVID-19 is an essential field in medicinal chemistry. Since the pandemic's beginning, several studies have reported the synthesis of novel organic compounds and their in silico interactions with the new coronavirus. Such computational studies are currently being applied to unveil the complexities of drug-target molecule interaction and also helping in developing new pharmacological treatments. This systematic review aims to provide an overview of studies describing the utilization of novel compounds as prospective drugs in the treatment of COVID-19.

Full-Spectrum Fluoromethyl Sulfonation via Modularized Multicomponent Coupling

Full-Spectrum Fluoromethyl Sulfonation via Modularized Multicomponent Coupling