In Silico Prediction of Plasmodium falciparum Cytoadherence Inhibitors That Disrupt Interaction between gC1qR-DBLß12 Complex.

Malaria causes about half a million deaths per year, mainly in children below 5 years of age. Cytoadherence of Plasmodium falciparum infected erythrocytes in brain and placenta has been linked to severe malaria and malarial related deaths. Cytoadherence is mediated by binding of human receptor gC1qR to the DBLß12 domain of a P. falciparum erythrocyte membrane protein family 1 (PfEMP1) protein. In the present work, molecular dynamic simulation was extensively studied for the gC1qR-DBLß12 complex. The stabilized protein complex was used to study the protein-protein interface interactions and mapping of interactive amino acid residues as hotspot were performed. Prediction of inhibitors were performed by using virtual protein-protein inhibitor database Timbal screening of about 15,000 compounds. In silico mutagenesis studies, binding profile and protein ligand interaction fingerprinting were used to strengthen the screening of the potential inhibitors of gC1qR-DBLß12 interface. Six compounds were selected and were further subjected to the MAIP analysis and ADMET studies. From these six compounds, the compounds 3, 5, and 6 were found to outperform on all screening criteria from the rest selected compounds. These compounds may provide novel drugs to treat and manage severe falciparum malaria. Additionally. the identified hotspots can be used in future for designing novel interventions for disruption of interface interactions, such as through peptides or vaccines. Futher in vitro and in vivo studies are required for the confirmation of these compounds as potential inhibitors of gC1qR-DBLß12 interaction.

Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: successful targets against some infectious diseases.

Parasitic diseases have a serious impact on the world in terms of health and economics and are responsible for worldwide mortality and morbidity. The present review features the hybrid targeting involving three main enzymes for the treatment of different parasitic diseases. The enzymes Dihydrofolate reductase, thymidylate synthase, and Serine hydroxy methyltransferase play an essential role in the folate pathway. The present review focuses on these enzymes, which can be targeted against several diseases. It shed light on the past, present, and future of these targets, and it can be assessed that these targets can play a significant role against several infectious diseases. For combating viral and protozoal infectious diseases, these targets in combination should be addressed.

Relative assessment of different statistical instruments and measures for the prediction of promising outcomes using docking, virtual screening and ADMET analysis against HIV-RT.

Reverse transcriptase is the most therapeutic target for the discovery of novel, potent, and non-toxic new anti-retroviral drugs. In the present work, various docking software such as Sybyl Surflex-Dock, OpenEye FRED, and Hermes GOLD were evaluated for their efficiency to reproduce known cognate inhibitors' conformations. Three metrics were used and compared to assess the performance of the applied scoring functions, i.e. enrichment factor, receiver operating characteristic (ROC) curves, and Bedroc analysis. Twelve different scoring functions of three softwares were used to assess their ability to rank the cognate ligand within the active site of its proteins. The extensive virtual screening task was performed on eight crystal structures, and the performance of docking and scoring was assessed by their ability to efficiently detect known active compounds enriched in the top-ranked of the list among a randomly selected dataset of the ten thousand compounds of the NCI database. The effectiveness of post-docking relaxation in Surflex was also evaluated. The top 20, 50, and 100 compounds were selected based on consensus scoring functions from all 48 proteins with different ligand complexes. Further, the shortlisted leads were subjected to ADMET via using Discovery Studio. The results further implicate the importance of various statistical tools that should be followed before large-scale virtual screening for the drug discovery process. In silico results demonstrating the experiment was successful. The study of the research covers the combinatorial in silico techniques such as benchmarking of the softwares and scoring functions, statistical tools applied for screening and different conformations of HIV-RT crystal structures for virtual screening with rigid and flexible molecular docking and molecular dynamics simulation approach. This study reveals a clear roadmap to identify novel scaffolds against HIV-RT for antiretroviral therapy, thus providing the remedial solutions of HIV related infections and other diseases caused by malfunctioning of the target protein.Communicated by Ramaswamy H. Sarma.

Computational Insights into the Interaction between Cytoadherence Receptor gC1qR and the DBLß12 Domain of a Plasmodium falciparum PfEMP1 Ligand.

Human receptor gC1qR is a 32 kD protein that mediates the cytoadherence of Plasmodium falciparum-infected erythrocytes (IEs) to human brain microvascular endothelial cells (HBMEC) and platelets. The cytoadherence of IEs to gC1qR has been associated with severe malaria symptoms. The cytoadherence to gC1qR is mediated by the Duffy binding-like ß12 (DBLß12) domain of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), PFD0020c. Here, we report the structural insights into the binding of the DBLß12 domain of PfEMP1 with the human receptor gC1qR using computational methods. A molecular model of the DBLß12 domain was generated and used for protein-protein docking with the host receptor gC1qR. The protein-protein docking revealed that the DBLß12 asymmetrically interacts with two subunits of the gC1qR trimer at the solution face of gC1qR. A total of 21 amino acid residues of DBLß12 interact with 26 amino acid residues in the gC1qR trimer through 99 nonbonding interactions and 4 hydrogen bonds. Comparative analysis of binding sites on the DBL domain fold for the two receptors gC1qR and ICAM1 showed that the two sites are distinct. This is the first study that provides structural insights into DBLß12 binding with its receptor gC1qR and may help in designing novel antisevere malaria interventions.

Simultaneous Determination of Chloroquine and Pyrimethamine with Cetirizine in an Active Form and Human Serum by RP-HPLC.

A simple, accurate and precise RP-HPLC method was developed for the simultaneous determination of chloroquine, pyrimethamine and cetirizine hydrochloride concentrations in bulk drug and human serum. The assay was performed using a mobile phase of methanol: water (70:30) at pH of 2.8 ± 0.05 on the Purospher C-18 column with UV detection at 230 nm and rosuvastatin used as an internal standard. The retention times observed for chloroquine, pyrimethamine and cetirizine hydrochloride were 3.5, 2.5 and 5.5 minutes, respectively. The method was found to be specific for the assayed drugs showing a linear response in the concentration range of 1-100 µg mL-1 with coefficients of determination values of (r = 0.999). The method was developed and validated according to ICH guidelines. The method was used to monitor the serum samples and was found to be sensitive for therapeutic purposes, showing the potential to be a useful tool for routine analysis in laboratories.

An overview of viruses discovered over the last decades and drug development for the current pandemic.

Since the discovery of the yellow fever virus in 1901, thus far, two hundred nineteen viral species are recognized as human pathogens. Each year, the number of viruses causing infections in humans increases, triggering epidemics and pandemics, such as the current COVID-19 pandemic. Pointing to bats as the natural host, in 2019, a genome highly identical to a bat coronavirus (COVID-19) spread all over the world, and the World Health Organization (WHO) officially confirmed it as a pandemic. The virus mainly spreads through the respiratory tract, uses angiotensin-converting enzyme 2 (ACE2) as a receptor, and is characterized by symptoms of fever, cough, and fatigue. Antivirals and vaccines have provided improvements in some cases, but the discovery of a new and diverse variety of viruses with outbreaks has posed a challenge in timely treatments for medical scientists. Currently, few specific antiviral strategies are being used, and many of the effective antiviral drugs and reported active molecules are under vital exploration. In this review, with the details of viral diseases, we summarize the current attempts in drug development, epidemiology, and the latest treatments and scientific advancements to combat the COVID-19 epidemic. Moreover, we discuss ways to reduce epidemics and pandemics in the near future.

Characterization of the Trypanosoma brucei Pteridine Reductase Active- Site using Computational Docking and Virtual Screening Techniques.

BACKGROUND: Human African trypanosomiasis is a fatal disease prevalent in approximately 36 sub-Saharan countries. Emerging reports of drug resistance in Trypanosoma brucei are a serious cause of concern as only limited drugs are available for the treatment of the disease. Pteridine reductase is an enzyme of Trypanosoma brucei. METHODS: It plays a critical role in the pterin metabolic pathway that is absolutely essential for its survival in the human host. The success of finding a potent inhibitor in structure-based drug design lies within the ability of computational tools to efficiently and accurately dock a ligand into the binding cavity of the target protein. Here we report the computational characterization of Trypanosoma brucei pteridine reductase (Tb-PR) active-site using twenty-four high-resolution co-crystal structures with various drugs. Structurally, the Tb-PR active site can be grouped in two clusters; one with high Root Mean Square Deviation (RMSD) of atomic positions and another with low RMSD of atomic positions. These clusters provide fresh insight for rational drug design against Tb-PR. Henceforth, the effect of several factors on docking accuracy, including ligand and protein flexibility were analyzed using Fred. RESULTS: The online server was used to analyze the side chain flexibility and four proteins were selected on the basis of results. The proteins were subjected to small-scale virtual screening using 85 compounds, and statistics were calculated using Bedroc and roc curves. The enrichment factor was also calculated for the proteins and scoring functions. The best scoring function was used to understand the ligand protein interactions with top common compounds of four proteins. In addition, we made a 3D structural comparison between the active site of Tb-PR and Leishmania major pteridine reductase (Lm- PR). We described key structural differences between Tb-PR and Lm-PR that can be exploited for rational drug design against these two human parasites. CONCLUSION: The results indicated that relying just on re-docking and cross-docking experiments for virtual screening of libraries isn't enough and results might be misleading. Hence it has been suggested that small scale virtual screening should be performed prior to large scale screening.

Role of PPAR receptor in different diseases and their ligands: Physiological importance and clinical implications.

The peroxisome proliferator-activated receptors (PPAR-α, PPAR-ß/δ, and PPAR-γ) are members of the nuclear receptor super-family, acting as ligand-inducible transcription factors and play crucial roles in glucose and lipid metabolism. These are a well-known receptor for diabetic therapy, not only influence the cardiovascular systems but are also expressed in many human solid tumors. For atherosclerosis, inflammation, and hypertension, the PPARs are considered as important therapeutic targets. Furthermore, it has been suggested that careful designing of partial agonists for PPARs, may show improvement with the side effects and also increase the therapeutic value for different diseases as cancer, inflammation and cardiovascular etc. This review summaries structural features of PPAR receptors, illustrates the method of PPAR modulator design, then analyzes recent dual- and pan-agonist with different therapeutic outcomes of the receptor to be used as a target for drugs in future. The advances in PPARs antagonists, their classification and structure-activity relationship are also summarized.

QSAR and Docking Studies on Piperidyl-cyclohexylurea Derivatives for Prediction of Selective and Potent Inhibitor of Matriptase.

BACKGROUND: QSAR models as PLS, GFA, and 3D were developed for a series of matriptase inhibitors using 35 piperidyl-cyclohexylurea compounds. The training and test sets were divided into a set of 28 and 8 compounds, respectively and the pki values of each compound were used in the analysis. METHODS: Docking and alignment methodologies were used to develop models in 3D QSAR. The best models among all were selected on the basis of regression statistics as r2, predictive r2 and Friedman Lack of fit measure. Hydrogen donors and rotatable bonds were found to be positively correlated properties for this target. The models were validated and used for the prediction of new compounds. Based on the predictions of 3D-QSAR model, 17 new compounds were prepared and their activities were predicted and compared with the active compound. Prediction of activities was performed for these 18 compounds using consensus results of all models. ADMET was also performed for the best-chosen compound and compared with the known active. RESULTS AND CONCLUSION: The developed model was able to validate the obtained results and can be successfully used to predict new potential and active compounds.

Reprofiling of full-length phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides toward antiproliferative agents: Synthesis, antiproliferative activity, and molecular docking study.

A series of phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides were synthesized via 1,3 dipolar cycloaddition and evaluated for their in vitro antiproliferative activity against the growth of cancer cell lines (MCF-7, A2780, HCT116) and normal non-transformed fibroblast (MRC5) using MTT assay. Synthesized compounds exhibited antiproliferative activity in the micromolar range. Compounds 11b showed the highest activity against MCF-7 cells (IC50 of 0.2344 µm). Cell cycle analysis was performed for compound 11b on MCF7 cells showing arrest of cells in the S phase. Molecular docking of synthesized compounds confirmed high affinity of these compounds to two different receptors for anticancer nucleosides on dCK, namely the 1P5Z and 2ZIA, showing scores higher than the cognate ligand for all tested compounds. All synthesized compounds were evaluated according to the Lipinski, Veber, and Opera rules, and all of them passed the evaluation showing excellent features, superior to reference drugs. In addition, ADME for all the synthesized compounds was predicted through a theoretical kinetic study using the discovery studio 3.1 software.

Identification of potent virtual leads and ADME prediction of isoxazolidine podophyllotoxin derivatives as topoisomerase II and tubulin inhibitors.

Towards the design of new class of podophyllotoxin to target topoisomerase II and tubulin as substantial target in cancer therapy, a series of isoxazolidine podophyllotoxin derivatives were designed. Topoisomerase in complex with etoposide and four ß-tubulin in complex with zampanolide, taxol, vinblastine or colchicine were used as targets using GOLD5.2.2 as a docking module. The revealed key structural features of the highest fitness into tubulin domain have been explained as follows: (1) trans orientation of the lactone (ring D) with 5a-ß, 8a-α configuration; (2) dioxolane in ring A; (3) free rotation of ring E; (4) α (R) or ß (S) configuration has equal fitness in position 5; (5) 4'-OMe; (6) phosphoramide linkage; (7) ethylene bridge between the phosphate and isoxazolidine ring; (8) benzyl moiety at N2-position of isoxazolidine ring; and (9) position 5 of isoxazolidine ring accommodated with 6-bromo-9H-purine, 2-amino-6H-purin-6-one, or N-(2-oxopyrimidin-4-yl) acetamide. All of these structural features are applicable for compounds to fit properly into topoisomerase II, except (1) ß (S) configuration has a higher score fitness than α (R) in position 5; (2) 4'-OH; and (3) position 5 of isoxazolidine ring accommodated better with 6-bromo-9H-purine, 2-amino-6H-purin-6-one or 7H-purin-6-amine. Computational ADMET and toxicity studies were in consensus with the docking results. Compounds holding ethylene bridge between phosphate and benzyl moiety at N2-position of isoxazolidine ring have the optimal pharmacokinetic properties and were calculated to be non-toxic. The predicted solubility profile for most of 4'-OMe containing compounds was good. This accomplished our aim in identifying promising new hits as antitumor agent with improved activity and less toxicity.

A combined 3D-QSAR and docking studies for the In-silico prediction of HIV-protease inhibitors.

BACKGROUND: Tremendous research from last twenty years has been pursued to cure human life against HIV virus. A large number of HIV protease inhibitors are in clinical trials but still it is an interesting target for researchers due to the viral ability to get mutated. Mutated viral strains led the drug ineffective but still used to increase the life span of HIV patients. RESULTS: In the present work, 3D-QSAR and docking studies were performed on a series of Danuravir derivatives, the most potent HIV- protease inhibitor known so far. Combined study of 3D-QSAR was applied for Danuravir derivatives using ligand-based and receptor-based protocols and generated models were compared. The results were in good agreement with the experimental results. Additionally, docking analysis of most active 32 and least active 46 compounds into wild type and mutated protein structures further verified our results. The 3D-QSAR and docking results revealed that compound 32 bind efficiently to the wild and mutated protein whereas, sufficient interactions were lost in compound 46. CONCLUSION: The combination of two computational techniques would helped to make a clear decision that compound 32 with well inhibitory activity bind more efficiently within the binding pocket even in case of mutant virus whereas compound 46 lost its interactions on mutation and marked as least active compound of the series. This is all due to the presence or absence of substituents on core structure, evaluated by 3D-QSAR studies. This set of information could be used to design highly potent drug candidates for both wild and mutated form of viruses.

Preparation and characterization of doxorubicin functionalized gold nanoparticles.

In this paper, we have presented the demonstration of gold nanoparticles (Au NPs) functionalized with an anticancer drug, doxorubicin. Doxorubicin was assembled on gold via amino group. The reaction proceeded under mild acidic conditions. Au NPs could not be adsorbed on doxorubicin in alkaline solution because amino group was not protonated. However, under acidic conditions, protonation created a positively charged amino group thus adsorption was easier. The interaction between Au colloids and doxorubicin is believed to be electrostatic. High-resolution TEM was used for visualization of nanoparticles, which were found to retain their average size and shape. The method, demonstrated that doxorubicin could be attached to Au NPs in a controlled manner. Our research laid the foundation of a linking methodology through which hybrid multi drug and receptor labeled NPs could be created, which might serve as an alternative design for nanosized drug-delivery systems.

Spectrophotometric determination of gabapentin in pharmaceutical formulations using ninhydrin and pi-acceptors.

Simple, rapid and sensitive spectrophotometric procedures are developed for the analysis of gabapentin in pure form as well as in their pharmaceutical formulations. The methods are based on the reaction of gabapentin as n-electron donor with ninhydrin and pi-acceptors namely, 2,3,5,6-tetrachloro-1,4-benzoquinone, chloranilic acid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetracyanoethylene and 7,7,8,8-tetracyanoquinodimethane. The obtained complexes were measured at 568, 230, 314, 304, 335 and 439 nm for ninhydrin, chloranil, Chloranilic acid, DDQ, TCNE and TCNQ respectively. The proposed procedures could be successfully applied to the determination of gabepentin with good recovery; percent ranged from 99.3 to 100.7 The association constants and free energy changes using Benesi-Hildebrand plots are also studied.