Virtual Screening Docking Research Articles

COMPUTATIONAL SCREENING OF POTENT ANTI-INFLAMMATORY COMPOUNDS FOR HUMAN MITOGEN-ACTIVATED PROTEIN KINASE: A COMPREHENSIVE AND COMBINED IN SILICO APPROACH

Objective: Inflammatory diseases have a serious impact on one’s life and represent a diverse group of ailments stemming from various causes and presenting in various forms. p38α of the mitogen-activated protein kinase family plays a crucial role in regulating inflammation, where the activation of this kinase initiates a cascade of events resulting in the production of proinflammatory mediators and cellular stress responses. In this context, attempts were made to identify potent small-molecule inhibitors of p38α and assess their binding affinity through molecular docking studies. Methods: From comprehensive reviews of several published reports, a few compounds, such as P38, P39, VPC00628, and N17, have shown substantial inhibitory activity toward p38α at various concentrations. Hence, these four compounds were chosen as lead compounds, and small-molecule libraries were constructed on the basis of their structural similarity. Next, virtual screening docking was performed to investigate the inhibitory potency of the four libraries toward the p38α isoforms (DFG-out and DFG-in), providing insights into their potential mechanisms of action. Results: In addition, a comprehensive analysis of physicochemical and pharmacokinetic properties was also performed for the identified hits from each library. Our findings have shown that, compared with those of the p38α DFG-in motif, the binding energies of the p38α DFG-out motif are greater. Conclusion: Furthermore, a few compounds from each library presented binding energies higher than those of their respective lead compounds, confirming their potential as novel therapeutic agents against inflammation.

Cheminformatic evaluation of the multi-protein binding potential of some diselenide derivatives: A plausible drug discovery approach for leishmaniasis

Over twelve million individuals worldwide suffer from leishmaniasis, and an additional billion people are at risk in places where the disease is prevalent. This work was motivated by the lack of vaccination against leishmaniasis and the shortcomings of current anti-leishmanial treatments. Large compound libraries can be screened using computational methods, which can also be used to analyze pharmacokinetic features, explore protein–ligand interactions, and quickly, accurately, and precisely create novel pharmacological entities. Virtual docking screening was performed to assess the multi-protein targeting capability of certain diselenides using four Leishmania protein targets—2XOX, 3SPX, 5ZWY, and 6K91. Following the Lipinski filter's screening of a subset of analogues, density functional theory (DFT), molecular dynamics (MD) simulation analysis, and ADMET profiles were used to profile the lead compounds. The overall average binding affinity of ligands to target proteins is as follows: 3SPX (− 184.998 kcal/mol) > 6K91 (− 180.114 kcal/mol) > 2XOX (− 176.581 kcal/mol) > 5ZWY (− 157.198 kcal/mol). The focus is on ligands that target all investigated proteins with binding scores greater than the average binding scores for the proteins as a whole for which seven compounds were identified that also showed higher MolDock scores than both reference drugs (Miltefosine and Pentamidine). Further screening showed four compounds (4, 7, 25, and 26) passed Lipinski’s test, making them orally bioavailable with excellent ADMET properties that compared well to both reference medications. The DFT analysis and MD simulation results indicate these compounds' favorability, stability, and reactivity in binding to the studied targets, 3SPX and 6K91 with 25_3SPX and 4_6K91 showing the highest binding free energy (MM-GBSA) of − 88.35 kcal/mol and − 90.29 kcal/mol respectively. Conclusively, the chosen diselenides could be developed as prospective anti-leishmanial pharmacological compounds or as useful scaffolds for creating more potent anti-leishmanial drugs.

Synthesis of Ethyl Pyrimidine-Quinolincarboxylates Selected from Virtual Screening as Enhanced Lactate Dehydrogenase (LDH) Inhibitors.

The inhibition of the hLDHA (human lactate dehydrogenase A) enzyme has been demonstrated to be of great importance in the treatment of cancer and other diseases, such as primary hyperoxalurias. In that regard, we have designed, using virtual docking screening, a novel family of ethyl pyrimidine-quinolinecarboxylate derivatives (13-18)(a-d) as enhanced hLDHA inhibitors. These inhibitors were synthesised through a convergent pathway by coupling the key ethyl 2-aminophenylquinoline-4-carboxylate scaffolds (7-12), which were prepared by Pfitzinger synthesis followed by a further esterification, to the different 4-aryl-2-chloropyrimidines (VIII(a-d)) under microwave irradiation at 150-170 °C in a green solvent. The values obtained from the hLDHA inhibition were in line with the preliminary of the preliminary docking results, the most potent ones being those with U-shaped disposition. Thirteen of them showed IC50 values lower than 5 μM, and for four of them (16a, 18b, 18c and 18d), IC50 ≈ 1 μM. Additionally, all compounds with IC50 < 10 μM were also tested against the hLDHB isoenzyme, resulting in three of them (15c, 15d and 16d) being selective to the A isoform, with their hLDHB IC50 > 100 μM, and the other thirteen behaving as double inhibitors.

A first-in-class dimethyl 2-acetamido terephthalate inhibitor targeting Conyza canadensis SHMT1 with a novel herbicidal mode-of-action

IntroductionHerbicide application is a highly efficiency method of weed control that boots agricultural output and assures food security. The development of novel herbicides focuses on improved bioactivity and new modes of action. The amino acid biosynthesis was validated as a promising novel mode of action for herbicidal compounds. However, the amino acid biosynthesis enzyme remains largely unexplored for herbicidal targets. ObjectivesSerine hydroxymethyl transferase (SHMT) is an essentialenzyme in the photorespiratory cycle. The study aims to explore Conyza canadensis SHMT1 (CcSHMT1) as a promising target for herbicide discovery. MethodsStructure determination of CcSHMT1 was resolved by X-ray crystallography. Virtual screening docking experiments were performed with Glide version 5.5. Novel derivatives of dimethyl 2-acetamido terephthalate were further designed, synthesized, and bioassay. The druggability of the inhibitor was evidenced by ultrastructural changes in mitochondria, in vivo and vitro enzyme activity assays, and genetics analysis. ResultsCcSHMT1 has a typical PLP-dependent enzyme 3D structure. The dimethyl 2-acetamido terephthalate-containing compounds had herbicidal activity. Dimethyl 2-(2-(4-(2-(4-bromo-2-chlorophenoxy) acetyl)piperazin-1-yl)acetamido) terephthalate (Compound 9ay, EC50 = 193.8 g a.i./ ha) exhibited the highest herbicidal activity on tested weed among the synthesized compounds. Compound 9ay had no obvious adverse effect on the growth of maize and honeybees. Compound 9ay was verified to target CcSHMT1 as an herbicide candidate. ConclusionA first-in-class CcSHMT1 inhibitor that could be developed as a potent herbicide with a new mode of action and provide an avenue for discovering novel inhibitors of pyridoxal-5-phosphate-dependent enzymes.

Structure-based virtual screening for discovery of paederosidic acid from Paederia scandens as novel P2Y14R antagonist

BackgroundThe activation of P2Y14 receptor (P2Y14R) promotes osteoclast formation and causes neuropathic pain, exhibiting possible link to osteoarthritis (OA). Given lack of P2Y14R antagonist, the present study aims to search a novel P2Y14R antagonist with low toxicity and high activity from natural products as a possible drug candidate in treatment of OA. MethodsThe role of P2Y14R on OA was verified using P2Y14R knockout (KO) rats. Molecular docking virtual screening strategy and activity test in P2Y14R stably-expressed HEK293 cells were used to screen target compound from natural product library. The MM/GBSA free energy calculation/decomposition technique was used to determine the principal interaction mechanism. Next, the binding of target compound to P2Y14R was examined using cellular thermal shift assay and drug affinity responsive target stability test. Finally, the therapeutic effect of target compound was performed in monosodium iodoacetate (MIA)-induced OA mouse model. To verify whether the effect of target compound was attributed to P2Y14R, we establish the osteoarthritis model in P2Y14R KO mice to perform pharmacodynamic evaluation. Importantly, to investigate the potential mechanism by which target compound attenuate OA, expressions of the major transcription factors involved in osteoclast differentiation were detected by western blot, while markers of nerve damage in dorsal root ganglion (DRG) were evaluated by RT-qPCR and immunofluorescence techniques. ResultsDeficiency of P2Y14R alleviated pain behavior and cartilage destruction in MIA-induced OA rats. 14 natural compounds were screened by Glide docking-based virtual screening, among which paederosidic acid exhibited the highest antagonistic activity to P2Y14R with IC50 of 8.287 μM. As a bioactive component extracted from Paederia scandens, paederosidic acid directly interacted with P2Y14R to enhance the thermostability and decrease the protease sensitivity of target protein, which significantly inhibited receptor activator for nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis. More importantly, paederosidic acid suppressed osteoclast formation by downregulating expressions of NFAT2 and ATP6V0D2, as well as relieved neuropathic pain by decreasing expressions of CGRP, CSF1 and galanin in DRG. ConclusionsPaederosidic acid targeted P2Y14R to improve OA through alleviating osteoclast formation and neuropathic pain, which provided an available strategy for developing novel drug leads for treatment of OA.

Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in "Super-Open" Conformation.

The Zika virus (ZIKV), a member of the Flaviviridae family, is considered a major health threat causing multiple cases of microcephaly in newborns and Guillain-Barré syndrome in adults. In this study, we targeted a transient, deep, and hydrophobic pocket of the "super-open" conformation of ZIKV NS2B-NS3 protease to overcome the limitations of the active site pocket. After virtual docking screening of approximately seven million compounds against the novel allosteric site, we selected the top six candidates and assessed them in enzymatic assays. Six candidates inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations. These six compounds, targeting the selected protease pocket conserved in ZIKV, serve as unique drug candidates and open new opportunities for possible treatment against several flavivirus infections.

Computational design, molecular properties, ADME, and toxicological analysis of substituted 2,6-diarylidene cyclohexanone analogs as potent pyridoxal kinase inhibitors.

Leishmaniasis is one of the tropical diseases which affects over 12 million people mainly in the tropical regions of the world and is caused by the leishmanial parasites transmitted by the female sand fly. The lack of vaccines to prevent leishmaniasis, as well as limitations of existing therapies necessitated this study which was focused on a combined virtual docking screening and 3-D QSAR modeling approach to design some diarylidene cyclohexanone analogs, while also performing pharmacokinetic analysis and Molecular Dynamic (MD) simulation to ascertain their drug-ability. As a result, the built 3-D QSAR model was found to satisfy the requirement of a good model with R2 = 0.9777, SDEC = 0.0593, F-test = 105.028, and Q2 LOO = 0.6592. The template (compound 9, MolDock score = - 161.064) and all seven newly designed analogs were found to possess higher docking scores than the reference drug (Pentamidine, Moldock score = - 137.827). The results of the pharmacokinetic analysis suggest 9 and the new molecules (9a, b, c, e, and f) as orally bioavailable with good ADME and safe toxicological profiles. These molecules also showed good binding interactions with the receptor (pyridoxal kinase). Additionally, the MD simulation result confirmed the stability of the tested protein-ligand complexes, with an estimated ∆G binding (MM/GBSA) of - 65.2177kcal/mol and -58.433kcal/mol for 9_6K91 and 9a_6K91 respectively. Hence, the new compounds, especially 9a could be considered potential anti-leishmanial inhibitors.

Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling.

The mechanistic target of rapamycin (mTOR) coordinates the growth and metabolism of eukaryotic cells with a central role in the regulation of many fundamental cellular processes. It is strongly connected to phosphatidylinositol 3-kinase (PI3K) and AKT signaling. Activation of the PI3K/AKT/mTOR pathway leads to a profound disruption in the control of cell growth and survival, which ultimately leads to competitive growth advantage, metastatic competence, angiogenesis and therapeutic resistance. To explore the common competitive adenosine triphosphate (ATP) inhibitors PI3K/AKT and PI3K/mTOR, we built a 2D mTOR-SAR model that predicted the bioactivity of AKT and PI3K inhibitors towards mTOR. The interaction of the best inhibitors was evaluated by docking analysis and compared to that of the standard AZ8055 and XL388 inhibitors. A mechanistic target of rapamycin-quantitative structure-activity relationship (mTOR-QSAR) model with a correlation coefficient (R2) of 0.80813 and a root mean square error of 0.17756 was obtained, validated and evaluated by a cross-validation leave-one-out method. The best predicted AKT and PI3K inhibitor pIC50 activities were 9.36-9.95 and 9.23-9.87 respectively. After docking and several comparisons, the inhibitors with better predictions showed better affinity and interaction with mTOR compared to AZ8055 and XL388, so we have found that 2 AKT inhibitors and 9 mTOR inhibitors met the Lipinski and Veber criteria and could be future drugs.

Bionics design of affinity peptide inhibitors for SARS-CoV-2 RBD to block SARS-CoV-2 RBD-ACE2 interactions

Coronavirus Disease 2019 (COVID-19), has already posed serious threats and impacts on the health of the population and the country's economy. Therefore, it is of great theoretical significance and practical application value to better understand the process of COVID-19 infection and develop effective therapeutic drugs. It is known that the receptor-binding structural domain (SARS-CoV-2 RBD) on the spike protein of the novel coronavirus directly mediates its interaction with the host receptor angiotensin-converting enzyme 2 (ACE2), and thus blocking SARS-CoV-2 RBD–ACE2 interaction is capable of inhibiting SARS-CoV-2 infection. Firstly, the interaction mechanism between SARS-CoV-2RBD-ACE2 was explored using molecular dynamics simulation (MD) coupled with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculation method. The results of energy analysis showed that the key residues R403, R408, K417, and Y505 of SARS-CoV-2 RBD and the key residues D30, E37, D38, and Y41 of ACE2 were identified. Therefore, according to the hotspot residues of ACE2 and their distribution, a short peptide library of high-affinity SARS-CoV-2 RBD was constructed. And by using molecular docking virtual screening, six short peptides including DDFEDY, DEFEDY, DEYEDY, DFVEDY, DFHEDY, and DSFEDY with high affinity for SARS-CoV-2 RBD were identified. The results of MD simulation further confirmed that DDFEDY, DEYEDY, and DFVEDY are expected to be effective inhibitors. Finally, the allergenicity, toxicity and solubility properties of the three peptide inhibitors were validated.

Discovery of anticancer agents with c-Met inhibitory potential by virtual and experimental screening of a chemical library

c-Met receptor tyrosine kinase has recently emerged as an important target with therapeutic implications in pancreatic cancer. In this study, we carried out a docking virtual screening on an in-house library of 441 synthesized compounds and selected the compounds with the best interactions with the c-Met protein to be subjected to experimental tests. Ten compounds belonging to 3 different classes of chemical structures were selected for this purpose and their antiproliferative effects were studied against 4 pancreatic ductal adenocarcinoma (PDAC) cell lines including AsPC-1, Suit-2, Panc-1 and Mia-Paca-2 cells, primary PDAC cells and also c-Met amplified EBC-1 cell line by sulforhodamine-B assay. Apoptosis induction was examined by Hoechst 33258 staining and annexin V-FITC/propidium iodide flow cytometric assay. The best compound was also assayed in three-dimensional cultures of AsPC-1 cells and its c-Met inhibitory potential was studied by immunoblotting and a homogenous time resolved fluorescence (HTRF) assay. The compound with a phenanthrotriazine hydrazinyl scaffold bearing nitrophenyl pendant (PhTH) was the most active derivative, with IC50 values in the range of 5–8 μM. This compound exerted antiproliferative effect against AsPC-1 cells also in the presence of hepatocyte growth factor (HGF). PhTH induced apoptosis, dose-dependently inhibited spheroid growth, inhibited c-Met activity in cell-free HTRF assay and also inhibited the phosphorylation of c-Met and its downstream effector ERK1/2 in AsPC-1 cells. Molecular docking and dynamics simulation and MM-PBSA analysis confirmed close interactions of PhTH with c-Met kinase domain. Some of the tested compounds in this study seem to be potential c-Met inhibitors with promising activities against PDAC cells.

Small Molecules Targeting SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) pandemic. Several variants of SARS-CoV-2 have emerged worldwide. These variants show different transmissibility infectivity due to mutations in the viral spike (S) glycoprotein that interacts with the human angiotensin-converting enzyme 2 (hACE2) receptor and facilitates viral entry into target cells. Despite the effective SARS-CoV-2 vaccines, we still need to identify selective antivirals, and the S glycoprotein is a key target to neutralize the virus. We hypothesize that small molecules could disrupt the interaction of S glycoprotein with hACE2 and inhibit viral entry. We analyzed the S glycoprotein-hACE2 complex structure (PDB: 7DF4) and created models for different viral variants using visual molecular dynamics (VMD) and molecular operating environment (MOE) programs. Moreover, we started the hits search by performing structure-based molecular docking virtual screening of commercially available small molecules against S glycoprotein models using OEDocking FRED-4.0.0.0 software. The FRED-4.0.0.0 Chemguass4 scoring function was used to rank the small molecules based on their affinities. The best candidate compounds were purchased and tested using a standard SARS-CoV-2 pseudotyped cell-based bioassay to investigate their antiviral activity. Three of these compounds, alone or in combination, showed antiviral selectivity. These small molecules may lead to an effective antiviral treatment or serve as probes to better understand the biology of SARS-CoV-2.

Molecular Docking Study, Drug-Likeness and Pharmacokinetic Properties (ADMET) Prediction of Some Novel Thiophene Derivatives as Salmonella typhi Inhibitors

Typhoid fever is a gram- negative bacterial infection caused by the bacterium called Salmonella Typhi, a rod-like shaped pathogen. Salmonella typhi is both food-born and water-born pathogen. This disease is affecting people in both developed and underdeveloped countries. In this research, geometry optimization was carried out using density functional theory (DFT) at B3LYP/6-31G* level of theory in finding the most stable structures of all the studied molecules. Molecular docking studies was carried out on novel thiophene derivatives (anti-typhoid agents) against S. Typhi target (DNA gyrase B) with the pdb ID: 1TM2 to virtually screened the studied molecules. The drug-likeness and pharmacokinetic properties of the investigated molecules were also evaluated using SWISSADME and pkCSM online web tools, respectively. The molecular docking virtual screening carried out on the anti-typhoid agents has explored their theoretical binding affinities (which ranges between -7.1 to 7.8 kcal/mol) and poses with the active sites of the S. Typhi target (DNA gyrase B). Compound A11 with the highest binding affinity of -7.8 Kcal/mol interacted with the following amino acid residues LYS35, THR247, ASP166, VAL164, TRP170, ALA222, PHE41, TR266, ASP116 and PHE41 in the active site of the receptor via conventional hydrogen bond, carbon hydrogen bond, hydrophobic and electrostatic interactions, respectively. The drug-likeness of the studied compounds showed good response to the Lipinski’s rule of five filtering criterion by not violating more than one of the filtering criterion thereby confirming their drug-likeness properties and oral bioavailability, respectively. Their ADMET properties showed that they were all absorbed in the intestinal at a rate above 80% and well distributed in the brain and the central nervous system. They were all found to be both substrate and inhibitors of 3A4 which indicated their metabolic properties. And based on their predicted total clearance values, they can be excreted out. All the reported compounds had a negative AMES toxicity which mean they were all non-toxic. With reference been made to an approved already existing anti-typhoid agent ciprofloxacin with a binding affinity of -7.3 Kcal/mol to the investigated molecules (most especially compound A11), All the reported molecules have higher binding affinities than the ciprofloxacin, having good pharmacokinetic properties therefore proves the tendency of their effectiveness when been administered as drug.

A novel PHD2 inhibitor acteoside from Cistanche tubulosa induces skeletal muscle mitophagy to improve cancer-related fatigue.

To study whether ACT exerts anti-fatigue activity against CRF by inducing skeletal muscle mitophagy via suppressing PHD2 to upregulate the HIF-1α/BNIP3 signaling pathway. In this study, the molecular docking virtual screening technique was used to screen active components in Cistanche tubulosa that act as potential PHD2 inhibitors; the preliminary verification was carried out by Surface plasmon resonance (SPR) technology. BALB/c mice were treated with Paclitaxel (PTX, 10mg/kg) and ACT (50, 100mg/kg) alone or in combination for 20 days. Fatigue-related behaviors, energy metabolism and skeletal muscle mitochondria were assessed. Murine C2C12 myoblast was cultured and differentiated; then, a C26 tumor cell-conditioned medium was added to induce cachexia. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential, mitochondrial microstructure and function, autophagy, PHD2/HIF-1 and PINK1/Parkin signal pathway proteins were analyzed. Then, interfering RNA technology was used to silence PHD2 and observe the efficacy of ACT. We demonstrated that ACT exerted good binding activity with PHD2; ACT administration ameliorated PTX-induced muscle fatigue-like behavior via improving muscle quality and mitochondria function, increasing mitophagy, upregulating COXIV, CytoC, PINK1, Parkin, HIF-1α and BNIP3 expression and inhibiting p62, LC3B, PHD2 and Beclin-1 expression. The protective effect of ACT disappeared after transfection with the PHD2 gene knockdown plasmid Egln-1-RNAi. These results suggest that ACT can improve CRF by promoting mitophagy via suppression of PHD2 to remove dysfunctional mitochondria, demonstrating that ACT has huge prospects for clinical application in CRF treatment.

Circular RNA NF1-419 Inhibits Proliferation and Induces Apoptosis by Regulating Lipid Metabolism in Astroglioma Cells.

Astroglioma is the most common primary tumor of the central nervous system. Currently, there is no effective treatment for astroglioma. In the present study, the extract (L3) from Ganoderma Lucidum (G. lucidum) was found to inhibit the growth of astroglioma U87 cells and change the expression of circular RNAs (circRNAs). One of these, including the circular NF1-419 (circNF1-419), was of interest because NF1 gene is a classic tumor suppressor gene. The functional role of circ-NF1-419 in the inhibition of astroglioma cells remains unknown. This study focuses on the role of circNF1-419 in functional abnormalities of U87 astroglioma cells and aims to elaborate on its regulatory mechanism. The circNF1-419 overexpressing U87 (U87-NF1-419) cells were constructed. We generated U87-NF1-419 to evaluate the role of circNF1-419 on cell cycle, apoptosis, proliferation, tumor growth and metabolic regulation. Finally, we used docking screening to identify compounds in G. lucidum extracts that target circ-419. U87-NF1-419 can promote cell apoptosis and regulate lipid metabolism through glycerophospholipid metabolism and retrograde endocannabinoid signaling. Further examinations revealed that the expression of metabolic regulators, such as L-type voltage-operated calcium channels (L-VOCC), phospholipase C-β3 (PLCβ3), Mucin1, cationic amino acid transporter 4 (CAT4), cationic amino acid transporter 1 (CAT1) and a kinase (PRKA) anchor protein 4 (AKAP4) was inhibited, while phosphatidylserine synthase 1 (PTDSS1) was enhanced in U87-NF1-419 cells. In vivo experiments showed that circNF1-419 inhibits tumor growth in BALB/C nude mice, and enhanced AKAP4 and PTDSS1 in tumor tissues. The virtual docking screening results supported that ganosporeric acid A, ganodermatriol, ganoderic acid B and α-D-Arabinofuranosyladenine in L3 could activate circNF1-419 in astroglioma treatment. This study indicated that circNF1-419 could be a therapeutic target for the clinical treatment of astroglioma. L3 from Ganoderma Lucidum (G. lucidum) could inhibit astroglioma growth by activating circNF1-419.

Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis

BackgroundLeishmaniasis is a neglected tropical disease caused by a group of protozoan of the genus Leishmania and transmitted to humans majorly through the bite of the female sand fly. It is prevalent in the tropical regions of the world especially in Africa and estimated to affect a population of about 12 million people annually. This theoretical study was therefore conducted in support of the search for more effective drug candidates for the treatment of leishmaniasis. This study focuses on the in silico activity prediction of twenty-eight (28) maleimides, structure-based design, molecular docking study and pharmacokinetics analysis of the newly designed maleimides. All the studied compounds were drawn using ChemDraw Ultra and optimized by the density functional theory (DFT) approach using B3LYP with 6-31G⁄ basis set.ResultsThe built QSAR model was found to satisfy the requirement of both internal and external validation tests for an acceptable QSAR model with R2 = 0.801, R2adj = 0.748, Q2cv = 0.710, R2test = 0.892 and cRp2 = 0.664 and has shown excellent prediction of the studied compounds. Among the five (5) protein receptors utilized for the virtual docking screening, pyridoxal kinase (PdxK) receptor (Pdb id = 6k91) showed the strongest binding interactions with compounds 14, 21 and 24 with the highest binding affinities of − 7.7, − 7.7 and − 7.8 kcal/mol, respectively. The selected templates (14, 21 and 24) were used to design twelve (12) new compounds (N1–N12) with higher docking scores than the templates. N7 (affinity = − 8.9 kcal/mol) and N12 (− 8.5 kcal/mol) showed higher binding scores than the reference drug pentamidine (− 8.10 kcal/mol), while N3 and N7–N12 showed higher predicted pIC50 than the templates. Also, the pharmacokinetics properties prediction revealed that the newly designed compounds, obeyed the Lipinski’s rule for oral bio-availability, showed high human intestinal absorption (HIA), low synthetic accessibility score, CNS and BBB permeability and were pharmacologically active.ConclusionsThe activities of the various maleimides were predicted excellently by the built QSAR model. Based on the pharmacokinetics and molecular docking studies therefore, the newly designed compounds are suggested for further practical evaluation and/or validation as potential drug candidates for the treatment of leishmaniasis.

Discovery of Bile Acid Derivatives as Potent ACE2 Activators by Virtual Screening and Essential Dynamics.

The angiotensin-converting enzyme II (ACE2) is a key molecular player in the regulation of vessel contraction, inflammation, and reduction of oxidative stress. In addition, ACE2 has assumed a prominent role in the fight against the COVID-19 pandemic-causing virus SARS-CoV-2, as it is the very first receptor in the host of the viral spike protein. The binding of the spike protein to ACE2 triggers a cascade of events that eventually leads the virus to enter the host cell and initiate its life cycle. At the same time, SARS-CoV-2 infection downregulates ACE2 expression especially in the lung, altering the biochemical signals regulated by the enzyme and contributing to the poor clinical prognosis characterizing the late stage of the COVID-19 disease. Despite its important biological role, a very limited number of ACE2 activators are known. Here, using a combined in silico and experimental approach, we show that ursodeoxycholic acid (UDCA) derivatives work as ACE2 activators. In detail, we have identified two potent ACE2 ligands, BAR107 and BAR708, through a docking virtual screening campaign and elucidated their mechanism of action from essential dynamics of the enzyme observed during microsecond molecular dynamics calculations. The in silico results were confirmed by in vitro pharmacological assays with the newly identified compounds showing ACE2 activity comparable to that of DIZE, the most potent ACE2 activator known so far. Our work provides structural insight into ACE2/ligand-binding interaction useful for the design of compounds with therapeutic potential against SARS-CoV-2 infection, inflammation, and other ACE2-related diseases.

Finding the First Potential Inhibitors of Shikimate Kinase from Methicillin Resistant Staphylococcus aureus through Computer-Assisted Drug Design.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important threat as it causes serious hospital and community acquired infections with deathly outcomes oftentimes, therefore, development of new treatments against this bacterium is a priority. Shikimate kinase, an enzyme in the shikimate pathway, is considered a good target for developing antimicrobial drugs; this is given because of its pathway, which is essential in bacteria whereas it is absent in mammals. In this work, a computer-assisted drug design strategy was used to report the first potentials inhibitors for Shikimate kinase from methicillin-resistant Staphylococcus aureus (SaSK), employing approximately 5 million compounds from ZINC15 database. Diverse filtering criteria, related to druglike characteristics and virtual docking screening in the shikimate binding site, were performed to select structurally diverse potential inhibitors from SaSK. Molecular dynamics simulations were performed to elucidate the dynamic behavior of each SaSK–ligand complex. The potential inhibitors formed important interactions with residues that are crucial for enzyme catalysis, such as Asp37, Arg61, Gly82, and Arg138. Therefore, the compounds reported provide valuable information and can be seen as the first step toward developing SaSK inhibitors in the search of new drugs against MRSA.

Application of lipidomics strategy to explore aging-related biomarkers and potential anti-aging mechanisms of ginseng

Aging often leads to an increase risk of age-related diseases, and the development of anti-aging drugs have become the trend and focus of the current scientific research. In this experiment, serum samples from healthy people of different ages were analyzed based on clinical lipidomics, and a total of 10 potential biomarkers in middle-aged and youth group, 20 biomarkers in the youth and the elderly group were obtained. Furthermore, dhSph and dhCer involved above may affect the aging process through sphingolipid metabolic pathway. As the first and rate-limiting step of catalyzing de novo sphingolipid pathway, SPT may play a key role in human anti-aging, which is revealed by lipidomics liposome tracer analysis. The potential active components in ginseng on SPT was further verified by molecular docking virtual screening and atomic force microscope. Four ingredients of ginseng may reduce the levels of metabolites dhSph and dhCer by inhibiting the activity of SPT, and play an anti-aging effect by affecting the sphingolipid metabolism pathway.A clinical trials registration number: ChiCTR1900026836.

Computer-aided design of some quinazoline analogues as epidermal growth factor receptor inhibitors

BackgroundThe treatment of epidermal growth factor receptor (EGFR)-muted non-small cell lung cancer (NSCLC) remains among the utmost important unachieved therapeutic need worldwide. Development of EGFR inhibitors to treat NSCLC mutations has been among the difficult tasks faced by researchers in this area. As such, there is a need to discover more EGFR inhibitors. The purpose of this work is to perform computer-aided/structure-based design of novel EGFR inhibitors, elucidate their nature of interactions with their target, and also assess their ADMET properties as well as their drug-likeness, respectively. Compound 17 with a highest binding affinity of −9.5kcal/mol was identified as the template hit compound using molecular docking virtual screening in our previous work. The compound interacted with the active site of the EGFR receptor via hydrogen bond with the following amino acid residues MET793, MET793, THR854, and ASP855 with bond distances of 2.61394 (Å), 2.18464 (Å), 2.57601 (Å), and 2.68794 (Å), respectively. It also interacted with the active site of the EGFR receptor via halogen bond (GLN791), hydrophobic bond (LEU718, CYS797, LYS745, ALA743, ALA743, and VAL726), electrostatic bond (LYS745), and others (MET766), respectively. Furthermore, from our previous study, the following descriptors (ATSC6m, ATSC8e, MATS7m, SpMax3_Bhp, SpMax5_Bhs, and MaxHBint10) contained in the reported model were found to be responsible for the inhibitory activities of the studied compounds. In this research, the template (compound 17) was modified manually by attaching halo-phenyl and halo-phenyl-amino rings on the para position of the flouro-nitro-benzamide moiety of the template compound, respectively.ResultsA computer-aided design/structure-based approach was used to design six new EGFR inhibitors using molecule 17 as the template compound for the design identified in our previously reported work. Molecular docking investigation was performed to elucidate the binding mode of these newly designed EGFR inhibitors with the binding pose of EGFR receptor (pdb code 4ZAU) and found to have better affinities which range from −9.5 to −10.4 kcal/mol than the template compound and gefitinib, the control, respectively. The ADMET property assessment of these newly designed EGFR inhibitors indicated that they were orally bioavailable with good absorption, distribution, metabolism, and excretory properties with no toxicity. And for their drug-likeness, they were seen to have a higher molecular weight which might be as a result of halo-phenyl-amino ring attachments. Based on this finding, halo-phenyl-amino rings might be responsible for the inhibitory activities of these newly designed compounds.ConclusionThe six newly designed EGFR inhibitors were found to have higher binding affinities toward their target EGFR receptor than the template compound and gefitinib which was used as the control in this research. They were seen to have good ADMET and drug-like properties which indicate that they might be orally bioavailable. Furthermore, according to their synthetic accessibility score, they can be easily synthesized in the laboratory because the values were found to be less than five which fall within the easy portion of the scale. Therefore, this research recommends that these newly designed EGFR inhibitors should be synthesized most especially those with higher binding affinities, good ADMET, and drug-likeness properties than the template compound.

Virtual Screening and Molecular Docking Studies for Discovery of Potential RNA-Dependent RNA Polymerase Inhibitors

The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Globally, this pandemic has affected over 111 million individuals and posed many health and economic challenges. Much research effort is dedicated to discovering new treatments to address the associated challenges and restrict the spread of SARS-CoV-2. Since SARS-CoV-2 is a positive-strand RNA virus, its replication requires the viral RNA-dependent RNA polymerase (RdRp) enzyme. In this study, we report the discovery of new potential RdRp enzyme inhibitors based on computer modeling and simulation methodologies. The antiviral ZINC database was utilized for covalent docking virtual screening followed by molecular inter-action analyses based on reported hot spots within the RdRp binding pocket (PDB: 7BV2). Eleven molecules, ZINC000014944915, ZINC000027556215, ZINC000013556344, ZINC000003589958, ZINC000003833965, ZINC000001642252, ZINC000028525778, ZINC000027557701, ZINC000013781295, ZINC000001651128 and ZINC000013473324, were shown to have the highest binding interactions. These molecules were further assessed by molecular dynamics (MD) simu-lations and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies. The results showed that all 11 molecules except ZINC000027557701 formed stable complexes with the viral RdRp and fell within the accepted ADMET parameters. The identified molecules can be used to design future potential RdRp inhibitors.