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The HGPRT AND XPRT ENZYMES FROM Leishmania donovani: MOLECULAR MODELING AND STUDY OF DUAL INHIBITORS.

The HGPRT AND XPRT ENZYMES FROM Leishmania donovani: MOLECULAR MODELING AND STUDY OF DUAL INHIBITORS.

Lucas Sousa Palmeira and Bruno Silva Andrade

Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) and Xanthine Phosphoribosyltransferase (XPRT) are classified in the type I PRTases family, which are responsible for purine recycling in the organism to which they belong. Protozoans of the order Kinetoplastidae such as Leishmania spp. cannot make de novo purine synthesis, and they have only the recovery route. The aim of this work was to perform molecular homology modeling of both HGPRT and XPRT targets, as well as to perform a virtual screening in order to search dual inhibitor for both enzymes. The 3D structures of HGPRT and XPRT from Leishmania donovani (Laveran and Mesnil, 1903) were constructed by the Swiss-Model Workspace, considering the best available crystallographic templates for both targets. The ROCS program (Openeye Scientific Software) was used to develop five pharmacophore structures, which were based on five active compounds for type I PRTases. Then, we submitted the pharmacophore structures to a ROCS searching a database of 57,000 compounds from natural sources extracted from ZINC DATABASE, in which a total number of 1,825 compounds (hits) for the five pharmacophores were returned. In a second step, we performed a receptor-based virtual screening (RVBS) using AutoDock Vina for molecular docking calculations. The 50 best compounds for both enzymes obtained affinity energies between -8.4 and -10.9 Kcal/mol, of which ZINC4096947, ZINC519733, ZINC485610, ZINC2150030 and ZINC58116 presented best values for both enzymes, as well as Lipinski’s rule of five characteristics. Molecular dynamics calculations revealed that the compound ZINC2150030 remained within the active site of both enzymes after 50 ns. Additionally, this inhibitor candidate can be tested in vitro and in vivo as a new treatment option for leishmaniasis.

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In Silico Evaluation of Some Flavonoids Honeybee Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors

In Silico Evaluation of Some Flavonoids Honeybee Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors

Heba Hashem

The huge attack of coronavirus disease (COVID-19) over all the world forces the researcher around the world to study the crystal structure of the main protease Mpro (3-chymotrypsin-like cysteine enzyme) which is the essential enzyme for coronavirus. The inhibition of this enzyme active site becomes the target of all scientists of drug discovery to overcome this disease. On the bases of this view, using the molecular modeling approach to evaluate the effect of different flavonoids compounds from honeybee and propolis as SARS-CoV-2 main protease inhibition using Schrodinger Maestro v10.1.
The presented study resulted in six main compounds possess high binding energy with the receptor active site of COVID-19 main protease.
Developing this study aim to be an effective way for the honeybee constitution as an inhibitors ligand for SARS-CoV-2 main protease inhibition and be in the medicinal study of anti-COVID-19 therapeutic drugs.

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MOLECULAR MODELING OF BUTYRYLCHOLINESTERASE INHIBITORS AS POTENTIAL DRUGS AGAINST ALZHEIMER’S DISEASE

MOLECULAR MODELING OF BUTYRYLCHOLINESTERASE INHIBITORS AS POTENTIAL DRUGS AGAINST ALZHEIMER’S DISEASE

Bárbara B. Novo, Joelma F. de Mesquita, Camilo H. S. Lima and Magaly G. Albuquerque

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide. According to the World Health Organization (WHO), it is estimated 152 million people worldwide will be affected by AD in 2050. Memory loss, a symptom of AD, is the result of a decrease of acetylcholine level in the brain, due to the increase in cholinesterases, mainly butyrylcholinesterase (BChE). Our study targets new potential BChE inhibitors, by molecular modeling, aiming to alleviate the symptoms from the acetylcholine deficit. We used two 3D structures of human BChE complexes with potent inhibitors, resolved by X-ray diffraction and available in the Protein Data Bank (PDB): 5DYW and 5NN0 (Košak et al., 2016, 2018). The inhibitors have a piperidine heterocycle showing (R) configuration at C3 of the piperidine ring, whose amino group is protonated, according to Košak et al. (2016, 2018). The construction of the 3D structures of the inhibitors (5HF601 in the 5DYW complex and 92H627 in the 5NN0 complex) was carried out in the Spartan’14, followed by geometry optimization and conformational analysis (systematic and random), using the MMFF94 force field. Molecular docking/redocking was performed on the DockThor server (https://dockthor.lncc.br/v2/), where the C-alpha from Gly116 (chain A) at the active site, was chosen as the center of the 20x20x20 Å box. The preliminary results indicate that, for both ligands, the poses with the best score refer to the structures where the absolute configurations of both, C3 and N of piperidine, are (S). In the case of C3, according to Košak et al., the configuration is (R), while the configuration of the protonated N is not described, probably due to the possibility of both configurations coexisting in equilibrium. Thus, our study suggests re-evaluating the configuration of these stereogenic centers. As a perspective, we will study the binding modes of other inhibitors.

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Molecular Docking and Optimization potentials of some phytoligands from Ficus sycomorus Fraction inhibiting Anopheles coluzzii Cytochrome CYP6P3 enzyme

Molecular Docking and Optimization potentials of some phytoligands from Ficus sycomorus Fraction inhibiting Anopheles coluzzii Cytochrome CYP6P3 enzyme

Abba Babandi, Chioma A Anosike, Abdullahi I Uba and Lawrance U.S Ezeayinka

A major obstacle in controlling malaria is mosquito’s resistance to insecticides, including pyrethroids. The resistance is mainly due to over-expression of detoxification enzymes such as Cytochrome P450. Insecticides tolerance can be reduced by inhibitors of P450s involved in insecticide detoxification. The ligand efficiency (LE) indexes were used as criteria in drug discovery and development decisions especially in fragment-based drug design (FBDD) perspective for efficient fragments optimization. Molecular docking study and computational modeling were employed using Glide XP software to determine the inhibitory potentials of some phytoligands isolated from Ficus sycomorus against Anopheles coluzzii P450 isoforms, CYP6P3, implicated in resistance. Homology model of the P450 enzyme was constructed using the Crystal structure of retinoic acid bound cyano bacterial CYP120A1 (PDB ID: 2VE3; Resolution: 2.1 Å). Potential LE and properties for optimization into formidable P450s inhibitors were analyzed using standard mathematical models. Compounds 5, 8 and 9 bound to the Heme iron of CYP6P3 at a distance of 3.14 Å, 2.47 Å and 2.59Å respectively, showing potential site of metabolism. The binding energies were 8.93, 10.44 and 12.56 Kcal/mol respectively showing non spontaneous interaction with the enzyme active site. The most common amino acid residues in the binding pocket were hydrophobic Phe123, Val310, Pro379 and Val380. These inhibitors were probably act by reversibly coordinating with the prosthetic heme iron atom and formation of quasi-irreversible complexes with the iron of the heme prosthetic group. The coordination of a strong ligand to the heme iron shifts the iron from the high- to the stable low-spin form and prevented oxygen binding to the heme. This change in the spin state occurs concomitantly with a change in the redox potential of the P450s, which eventually inhibit the catalytic activities. The LE index showed high potential of these compounds to form core fragment for optimization into a potent P450s inhibitors.