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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.

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VIRTUAL SCREENING USING APPROVED DRUGS: IN SILICO EVALUATION OF ANTI HAT POTENTIALS

VIRTUAL SCREENING USING APPROVED DRUGS: IN SILICO EVALUATION OF ANTI HAT POTENTIALS

Raíssa Lima and Manuela Silva

Human African Trypanosomiasis (HAT), also called sleeping sickness, is a neglected disease caused by the parasite Trypanosoma brucei. The problem with HAT is that the drugs used in the treatment have several adverse effects (personality changes, psychosis and hyponatremia), negatively influencing therapeutic adherence. The objective of the work is to find potential substances that can act by inhibiting the 24-c-sterol-methytranferase (SMT) protein, which participates in the ergosterol biosynthesis, an important metabolic pathway for the parasite. First, the PDBid structures were prepared: 3BUS (a transferase of Lentzea aerocolonigenes, used in the prediction of the TbSMT model) and the SAH cofactor (S-Adenosyl-L-homocysteine). We used PDB2PQR web server for protonation of 3BUS (Amber force field) and OpenBabel was used for the ligand, both at pH 7.4. The addition of hydrogens, addition of Gasteiger charge and Grid formulation (center x: 15.278; y: 28.139; z: 30.662; and size x: 60; y: 60; z: 54;) was done using AutoDock Tools and Chimera . For redocking, the AutodDock Vina was used, testing 12 different exhaustiveness. The result that had the lowest RMSD (calculated with OpenBabel) was exhaustiveness 48, 1,355 Å. With the parameters validated, the docking was done between the TbSMT structure (obtained through previous work) and the shape of the cofactor before the action of the enzyme, SAM (S-Adenosyl-L-methionine). For this, SAM was removed from the PDBid: 4DF3 crystal (a transferase of Aeropyrum pernix). With the SMT structure containing the SAM cofactor, virtual screening was performed using a database present at ZINC, World. We found 10 promising substances classified by binding energy.

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NAMPT SNPs ASSOCIATED WITH VISFATIN/NAMPT LEVELS LOCATED NEARBY A PUTATIVE ENHANCER REGION ACTIVATED BY METFORMIN

NAMPT SNPs ASSOCIATED WITH VISFATIN/NAMPT LEVELS LOCATED NEARBY A PUTATIVE ENHANCER REGION ACTIVATED BY METFORMIN

Daniela Pereira, Lídia Coura and Marcelo Luizon

Nicotinamide phosphoribosyltransferase (NAMPT) is a potential therapeutic biomarker or target for several diseases. NAMPT is activated by Metformin, the first-line therapy for type 2 diabetes, and it is also used as a treatment for other diseases. Moreover, the single nucleotide polymorphism (SNP) rs1319501 in NAMPT promoter region were found to be associated with plasma NAMPT levels, and tightly linked with the SNPs rs9770242 and rs61330082, which are located ~1,500bp upstream from the NAMPT transcription start site. However, these noncoding SNPs may overlap with functional regulatory elements, such as enhancers. Thus, we searched for metformin-responsive regulatory elements in the NAMPT locus, and linked SNPs within them which may be associated with NAMPT levels. First, we examined publicly available ChIP-seq data for active (H3K27ac) and silenced (H3K27me3) histone marks on human hepatocytes treated with metformin, GeneHancer to identify active regulatory elements (enhancers and promoters), and several cis-regulatory elements assignment tools from the Encyclopedia of DNA Elements (ENCODE) to identify enhancers around the NAMPT locus. Next, we performed the functional annotation of noncoding SNPs located in the NAMPT locus using the Genotype-Tissue Expression (GTEx) project data for SNPs linked to NAMPT expression. The SNPs rs1319501, rs9770242 and rs61330082 overlap with a metformin-responsive region enriched for the active histone mark H3K27ac upon metformin treatment, which is located nearby an enhancer element according to GeneHancer (GH07J106288). Interestingly, rs61330082 and rs11977021 were in perfect linkage disequilibrium in a cohort of severely obese children and are associated with visfatin level and adverse cardiometabolic parameters. According to GTEx, these SNPs are eQTLs for NAMPT expression in heart tissue. These data support that noncoding variation within a metformin-activated enhancer may increase NAMPT expression. The perspectives are to functionally characterize these noncoding NAMPT SNPs, which could help to predict NAMPT levels in patients with type 2 diabetes treated with Metformin.