Ligand-Based Pharmacophore Modeling Using Novel 3D Pharmacophore Signatures. 2018

Alina Kutlushina, and Aigul Khakimova, and Timur Madzhidov, and Pavel Polishchuk
A.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlevskaya Str. 18, 420008 Kazan, Russia. Alina.Kutlushina@pharminnotech.com.

Pharmacophore modeling is a widely used strategy for finding new hit molecules. Since not all protein targets have available 3D structures, ligand-based approaches are still useful. Currently, there are just a few free ligand-based pharmacophore modeling tools, and these have a lot of restrictions, e.g., using a template molecule for alignment. We developed a new approach to 3D pharmacophore representation and matching which does not require pharmacophore alignment. This representation can be used to quickly find identical pharmacophores in a given set. Based on this representation, a 3D pharmacophore ligand-based modeling approach to search for pharmacophores which preferably match active compounds and do not match inactive ones was developed. The approach searches for 3D pharmacophore models starting from 2D structures of available active and inactive compounds. The implemented approach was successfully applied for several retrospective studies. The results were compared to a 2D similarity search, demonstrating some of the advantages of the developed 3D pharmacophore models. Also, the generated 3D pharmacophore models were able to match the 3D poses of known ligands from their protein-ligand complexes, confirming the validity of the models. The developed approach is available as an open-source software tool: http://www.qsar4u.com/pages/pmapper.php and https://github.com/meddwl/psearch.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D002800 Cholinesterase Inhibitors Drugs that inhibit cholinesterases. The neurotransmitter ACETYLCHOLINE is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. Acetylcholinesterase Inhibitor,Acetylcholinesterase Inhibitors,Anti-Cholinesterase,Anticholinesterase,Anticholinesterase Agent,Anticholinesterase Agents,Anticholinesterase Drug,Cholinesterase Inhibitor,Anti-Cholinesterases,Anticholinesterase Drugs,Anticholinesterases,Cholinesterase Inhibitors, Irreversible,Cholinesterase Inhibitors, Reversible,Agent, Anticholinesterase,Agents, Anticholinesterase,Anti Cholinesterase,Anti Cholinesterases,Drug, Anticholinesterase,Drugs, Anticholinesterase,Inhibitor, Acetylcholinesterase,Inhibitor, Cholinesterase,Inhibitors, Acetylcholinesterase,Inhibitors, Cholinesterase,Inhibitors, Irreversible Cholinesterase,Inhibitors, Reversible Cholinesterase,Irreversible Cholinesterase Inhibitors,Reversible Cholinesterase Inhibitors
D058917 Adenosine A2 Receptor Antagonists Compounds that selectively bind to and block the activation of ADENOSINE A2 RECEPTORS. Adenosine A2A Receptor Antagonists,Adenosine A2B Receptor Antagonists
D065692 Cytochrome P-450 CYP3A Inhibitors Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP3A. CYP3A Inhibitor,CYP3A5 Inhibitor,CYP3A7 Inhibitor,Cyp3A4 Inhibitor,Cytochrome P-450 CYP3A Inhibitor,Cytochrome P-450 CYP3A4 Inhibitor,Cytochrome P-450 CYP3A5 Inhibitor,Cytochrome P-450 CYP3A7 Inhibitor,P450 CYP3A Inhibitor,P450 CYP3A4 Inhibitor,P450 CYP3A5 Inhibitor,P450 CYP3A7 Inhibitor,CYP3A Inhibitors,CYP3A4 Inhibitors,CYP3A5 Inhibitors,CYP3A7 Inhibitors,Cytochrome P-450 CYP3A4 Inhibitors,Cytochrome P-450 CYP3A5 Inhibitors,Cytochrome P-450 CYP3A7 Inhibitors,P450 CYP3A Inhibitors,P450 CYP3A4 Inhibitors,P450 CYP3A5 Inhibitors,P450 CYP3A7 Inhibitors,CYP3A Inhibitor, P450,CYP3A4 Inhibitor, P450,CYP3A5 Inhibitor, P450,CYP3A5 Inhibitors, P450,CYP3A7 Inhibitor, P450,CYP3A7 Inhibitors, P450,Cytochrome P 450 CYP3A Inhibitor,Cytochrome P 450 CYP3A Inhibitors,Cytochrome P 450 CYP3A4 Inhibitor,Cytochrome P 450 CYP3A4 Inhibitors,Cytochrome P 450 CYP3A5 Inhibitor,Cytochrome P 450 CYP3A5 Inhibitors,Cytochrome P 450 CYP3A7 Inhibitor,Cytochrome P 450 CYP3A7 Inhibitors,Inhibitor, CYP3A,Inhibitor, CYP3A5,Inhibitor, CYP3A7,Inhibitor, Cyp3A4,Inhibitor, P450 CYP3A,Inhibitor, P450 CYP3A4,Inhibitor, P450 CYP3A5,Inhibitor, P450 CYP3A7,Inhibitors, CYP3A,Inhibitors, CYP3A4,Inhibitors, CYP3A5,Inhibitors, CYP3A7,Inhibitors, P450 CYP3A,Inhibitors, P450 CYP3A4,Inhibitors, P450 CYP3A7

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