Diabetes is a chronic disease characterized by hyperglycemia, accompanied by a disruption of carbohydrate and protein metabolisms resulting from a lack of secretion and/or action of insulin. Various therapeutic and preventive means are proposed. Currently, there are few drugs that can counteract the development of associated pathologies. It is in this context that this In Silico Studies of New α-Amylases (1B2Y) and α-Glucosidases (3WY1) Inhibitory molecular structures is carried out in order to propose new molecular structures that would be more effectives. Thanks to the powerful software for virtual screening (InfiniSee) and molecular docking (SeeSAR), which we have been licensed free of charge for 01 years by BioSolveIT, our study project was as easy as we had not hoped. Indeed, one of our previous studies allowed us to identify 71 molecules of three different series of chemical compounds, as inhibitors of 1B2Y enzyme and 3WY1 enzyme. The relationship between the electronic structure and the inhibitory activity of these molecules has been studied using the Klopman-Peradejordi-Gomez QSAR approach. Five models of pharmacophores have been proposed showing the important sites of molecules and the types of interactions in which they could be involved with residues of active protein sites. We proposed five new hypothetical molecules and their virtual screening was carried out using InfiniSee software with parameters such as : Target Similarity (1), Minimum Similarity (0.86) and Total Diversity (0.90). One thousand ninety-eight (1098) new molecular structures with similar chemical properties were obtained, including 521 for the 1B2Y enzyme and 577 for the 3WY1 enzyme. The crystallographic structures of the two proteins were then downloaded using SeeSAR’s Protein Mode (PDB) function and their active sites were automatically detected; the ligands complexed with these two receptors were extracted then the missing residues were added with ease. Since the SeeSAR software has the most important parameters of ADMET-Tox, we proceed directly to the molecular docking of the 1098 molecules respecting the parameters such as: maximum number of poses (10), clash tolerance (standard), allowed ring conformations (chair form). Then, an estimation of the affinities of the poses with the active sites was calculated thanks to the HYDE function implemented in SeeSAR. With ADMET-Tox parameters such as: 2C9 pKi, BBB category, HIA category, logP, logD, hERG pIC50, MW de SeeSAR, 143 molecules showed better activity against the 1B2Y enzyme and 137 molecules against the 3WY1 enzyme. Finally, five molecular structures were selected under the pretext that they presented the five best poses with the most stable conformations within the active sites.
After 1 year, Maounou Boris has achieved the following goals:
- The Quantitative Structure-Activity Relationship study of the 71 molecules of the three different series of chemical compounds was successfully carried out using the Klopman-Peradejordi-Gomez (KPG) QSAR approach. First, we selected from the renowned reviews the three series of molecules with well-known experimental IC50 values. For each series of molecules, all chemical compounds have the same common skeleton. We then proceed to the geometric optimization of the molecules and the calculations of the associated energies (single point) thanks to a set of GAUSSIAN program. Local atomic reactivity indices were calculated with the D-CENT-QSAR program. Five linear equations of multiple regression were developed from Statistica.10. Finally we have proceeded to the variable by variable analysis (VpV) of each of the equations to propose the five 2D partial pharmacophores.
- The virtual screening of the hypothetical molecules obtained from the five 2D partial pharmacophores was successfully carried out thanks to the InfiniSee software of BioSolveIT. Using this powerful software, six different chemical databases were selected (eXplore, Freedom Space, REAL Space, GalaXi, CHEMriya and KnowledgeSpace) and filtering parameters such as: Target Similarity (1), Minimum Similarity (0.86) and Total Diversity (0.90) were considered for better screening according to our project objectives. 1098 molecules with the similar chemical properties have been successfully obtained.
- We have successfully and easily realized the molecular docking and the study of the ADMET-Tox properties of hypothetical molecules obtained from the virtual screening thanks to the SeeSAR software of BioSolveIT. Thanks to SeeSAR’s Protein Mode (PDB) function, both protein crystallographic structures have been downloaded. The ligands of interest were then extracted. With the SeeSAR Binding Site mode, the active protein cavities were automatically detected and the empty pockets were filled with the missing residues. The proteins are switched to Docking mode for molecular docking. Affinity estimates were then calculated using SeeSAR’s HYDE feature. Excel files have been created based on enzymes in order to eliminate certain molecules taking into account the ADMET-Tox parameters that we have defined.