MolGpka: A Web Server for Small Molecule pK_a Prediction Using a Graph-Convolutional Neural Network

Abstract

pK a is an important property in the lead optimization process since the charge state of a molecule in physiologic pH plays a critical role in its biological activity, solubility, membrane permeability, metabolism, and toxicity. Accurate and fast estimation of small molecule pK a is vital during the drug discovery process. We present MolGpKa, a web server for pK a prediction using a graph-convolutional neural network model. The model works by learning pK a related chemical patterns automatically and building reliable predictors with learned features. ACD/pK a data for 1.6 million compounds from the ChEMBL database was used for model training. We found that the performance of the model is better than machine learning models built with human-engineered fingerprints. Detailed analysis shows that the substitution effect on pK a is well learned by the model. MolGpKa is a handy tool for the rapid estimation of pK a during the ligand design process. The MolGpKa server is freely available to researchers and can be accessed at https://xundrug.cn/molgpka.

Identification of a Novel Delta Opioid Receptor Agonist Chemotype with Potential Negative Allosteric Modulator Capabilities

“…The scaffold lacks a basic protonated amine, which is generally considered a hallmark feature of opioid ligands, needed to form a stable salt-bridge with aspartate D 3.32 [ 22 ]. Using MolgpKa [ 26 ], the predicted pKa of the basic nitrogen in the pyrazole ring of compound 1 is 1.4, in sharp contrast with the pKa for protonated basic amines that is closer to physiological pH. A second interesting feature of compound 1 is the apparent negative allosteric modulation of the endogenous agonist Leu-enkephalin.…”

Phenolic Thiazoles with Antioxidant and Antiradical Activity. Synthesis, In Vitro Evaluation, Toxicity, Electrochemical Behavior, Quantum Studies and Antimicrobial Screening

“…Using the Swiss ADME web tool, some molecular properties were calculated, such as octanol-water partition coefficient, topological polar surface area, gastrointestinal absorption after oral administration, and octanol-water partition coefficients, as part of Lipinski’s rule of five [ 40 , 41 , 42 ]. pKa of the compounds was assessed using MolGpka [ 43 ]. The calculation of the molecular properties was performed for each parent compound of the final compounds 5a-b , 6a-b , 7a-b , and 8a-b , without the corresponding hydrohalide acid.…”

A highly sensitive cell-based luciferase assay for high-throughput automated screening of SARS-CoV-2 nsp5/3CLpro inhibitors

“…MolGpka, a graph-convolutional based method for pKa calculation (https://xundrug.cn/molgpka) [71], was used to calculate the pKa of hit molecules, and the Molinspiration software (https://www.molinspiration.com/) was used to predict their octanol/water partition coefficient (cLogP).…”