Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2B R Ligands

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Krzysztof RatajGyorgy M Keseru

Abstract

The identification of subtype-selective GPCR (G-protein coupled receptor) ligands is a challenging task. In this study, we developed a computational protocol to find compounds with 5-HT2BR versus 5-HT1BR selectivity. Our approach employs the hierarchical combination of machine learning methods, docking, and multiple scoring methods. First, we applied machine learning tools to filter a large database of druglike compounds by the new Neighbouring Substructures Fingerprint (NSFP). This two-dimensional fingerprint contains information on the connectivity of the substructural features of a compound. Preselected subsets of the database were then subjected to docking calculations. The main indicators of compounds’ selectivity were their different interactions with the secondary binding pockets of both target proteins, while binding modes within the orthosteric binding pocket were preserved. The combined methodology of ligand-based and structure-based methods was validated prospectively, resulting in the identification of hits with nanomolar affinity and ten-fold to ten thousand-fold selectivities.

References

Sep 1, 1994·Naunyn-Schmiedeberg's Archives of Pharmacology·J R Fozard, H O Kalkman
May 1, 1996·The European Journal of Neuroscience·K SchmuckH Lubbert
Feb 9, 1999·Progress in Drug Research. Fortschritte Der Arzneimittelforschung. Progrès Des Recherches Pharmaceutiques·K W JohnsonM L Cohen
Aug 24, 1999·British Journal of Pharmacology·D W BonhausG R Martin
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Aug 5, 2000·Science·K PalczewskiM Miyano
Apr 27, 2004·Cardiovascular Drugs and Therapy·Anikó KovácsGábor Szénási
Dec 29, 2006·Molecular Pharmacology·G Enrico RovatiRichard R Neubig
Sep 28, 2007·Current Pharmaceutical Design·Sean L Kitson
Oct 24, 2007·Nature·Søren G F RasmussenBrian K Kobilka
Sep 12, 2008·Bioinformatics·Justin Klekota, Frederick P Roth
Mar 25, 2009·Bioorganic & Medicinal Chemistry Letters·Neil MossMark Whitaker
Dec 24, 2009·Current Pharmaceutical Design·Stefano CostanziKenneth A Jacobson
Jul 23, 2011·Proceedings of the National Academy of Sciences of the United States of America·Ron O DrorDavid E Shaw
Feb 24, 2012·Nature·Andrew C KruseBrian K Kobilka
Feb 5, 2013·Cell·Rie NygaardBrian K Kobilka
Mar 23, 2013·Science·Daniel WackerRaymond C Stevens
May 17, 2013·Current Topics in Medicinal Chemistry·Terry-Elinor ReidXiang Simon Wang
Nov 12, 2013·Nucleic Acids Research·A Patrícia BentoJohn P Overington
Dec 21, 2013·Science·Wei LiuVadim Cherezov
Sep 16, 2014·ACS Medicinal Chemistry Letters·Márton VassGyörgy M Keserű
Jan 21, 2015·Pharmacology & Therapeutics·John D McCorvy, Bryan L Roth
Feb 11, 2015·BioMed Research International·Wiebke JanssenRalph Theo Schermuly
Jan 14, 2016·Journal of Chemical Information and Modeling·Adam KelemenGyorgy M Keseru
Jan 28, 2017·Cell·Daniel WackerBryan L Roth
May 24, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Krzysztof RatajAndrzej J Bojarski

❮ Previous
Next ❯

Citations

Nov 8, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·F Javier Luque
Jan 10, 2021·International Journal of Molecular Sciences·Katrin DenzingerMarcel Bermudez
Mar 2, 2021·Experimental Biology and Medicine·Siyu ZhuJing An
Sep 22, 2020·Biochemistry·Christian D-T NielsenAgostino Cilibrizzi
Oct 28, 2019·Journal of Chemical Information and Modeling·Yan LiRenxiao Wang

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray
in silico methods
competition binding

Software Mentioned

ChEMBL
LigPrep
learn
NSFP
PrepWiz
scikit
Schrödinger
PubChem
Python
Glide

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.