AlphaMol-Alpha Molecular Technology Co., Ltd.

Our science

GPCR molecular research

Membrane proteins

in particular G protein-coupled receptors (GPCRs), are the most important drug targets. As an example, about 40% of the clinically used drugs are targeting GPCRs.
In some pharmaceutical companies, this figure can be even as high as 70-80%. Therefore, the understanding of membrane protein functions is of fundamental importance for modern drug discovery.

AlphaMol

Our team members have made important contributions to understand receptor mediated signalling at the molecular level. They have published many innovative works in top journals including Cell, Nature,
Nature Communications, Chemical Science, Trends in Biochemical Sciences, Angewandte Chemie and others.

Publication

Time

Dissertation

Periodical

Link

2024

The structure and function of olfactory receptors

Trends in Pharm Sci

https://doi.org/10.1016/j.tips.2024.01.004

2023

Molecular basis of ligand selectivity for melatonin receptors

RSC Adv

https://doi.org/10.1039/D2RA06693A

2021

The role of metal ions in GPCR signaling and drug discovery

Computational Molecular Science

https://doi.org/10.1002/WCMS.1565

2020

Structural basis of CXC chemokine receptor 2 activation and signalling

Nature

https://doi.org/10.1038/s41586-020-2492-5

2020

Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures

Cell

https://doi.org/10.1016/j.cell.2020.01.008

2020

Enhancing the Signaling of GPCRs via Orthosteric Ions

ACS Central Science

https://doi.org/10.1021/acscentsci.9b01247

2019

New binding sites, new opportunities for GPCR drug discovery

Trends in Biochemical Sciences

https://doi.org/10.1016/j.tibs.2018.11.011

2018

Exploring a new ligand binding site of G protein-coupled receptors

Chemical Science

https://doi.org/10.1039/C8SC01680A

2019

New binding sites, new opportunities for GPCR drug discovery

Trends in Biochemical Sciences

https://doi.org/10.1016/j.tibs.2018.11.011

2018

5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology

Cell

https://doi.org/10.1016/j.cell.2018.01.001

2017

Designing Safer Analgesics via µ-Opioid Receptor Pathways

Trends in Pharmacological Sciences

https://doi.org/10.1016/j.tips.2017.08.004

2016

Mechanistic Studies on the Stereoselectivity of the Serotonin 5-HT1A Receptor

Angewandte Chemie Int Ed Engl

https://doi.org/10.1002/anie.201603766

2016

The Molecular Mechanism of P2Y1 Receptor Activation

Angewandte Chemie Int Ed Engl

https://doi.org/10.1002/anie.201605147

2015

The Mechanism of Ligand-Induced Activation or Inhibition of mu- and kappa-Opioid Receptors

Angewandte Chemie Int Ed Engl

https://doi.org/10.1002/anie.201501742

2014

W246 Opens a Gate for a Continuous Intrinsic Water Pathway during Activation of the Adenosine A Receptor

Angewandte Chemie Int Ed Engl

https://doi.org/10.1002/anie.201409679

2014

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

Nature Communications

https://doi.org/10.1038/ncomms5733

2014

Advances in GPCR modeling evaluated by the GPCR Dock 2013 assessment: meeting new challenges

Structure

https://doi.org/10.1016/j.str.2014.06.012

Innovative GPCR biotesting

G protein-coupled receptors

G protein-coupled receptors (GPCRs) are the most important drug targets, of which about 40% of the marketed drugs are targeting GPCRs.
As a membrane protein, the biological activity testing for GPCR drug discovery is still a challenging task. Many difficulties remain to be resolved including: (1) testing drug activity without labeling (2) measuring GPCR/G-protein interaction directly instead of determining that of cAMP or Ca2+ signaling in an indirect way (3) measuring kinetic properties of GPCR drug molecules and (4) differentiating G protein types inside cells.

In this regard, the team member of AlphaMol developed a series of innovative biochip technologies to overcome the hurdle in GPCR drug discovery in the past 20 years. Such breakthrough facilitates the process of GPCR drug discovery in a much more accurate and efficient way.

Publication

Time

Dissertation

Periodical

Link

2018

Single-vesicle assays using liposomes and cell-derived vesicles: from modeling complex membrane processes to synthetic biology and biomedical applications

Chemical reviews

https://doi.org/10.1021/acs.chemrev.7b00777

2011

Activation of G-protein-coupled receptors in cell-derived plasma membranes supported on porous beads

JACS

https://doi.org/10.1021/ja205302g

1999

Micropatterned immobilization of a G protein–coupled receptor and direct detection of G protein activation

Nature Biotechnology

https://doi.org/10.1038/15090

1998

Incorporation of Rhodopsin in Laterally Structured Supported Membranes: Observation of Transducin Activation with Spatially and Time-Resolved Surface Plasmon Resonance†

Biochemistry

https://doi.org/10.1021/bi971564r

New drug discovery

AlphaMol

Modern drug discovery and development is a complicated process, which costs about $2-3 billion and lasts for 12 years on average. How to decrease the costs and speed up the process is the challenge. Computational biology and Artificial Intelligence, combined with new technologies in experimental drug screening, are expected to make the hunt for new drugs quicker, cheaper and more efficient.
Our team has established a sophisticated computer-aided drug discovery platform, which combines Artificial Intelligence, WebGL, cloud computing and big data. It can perform a wide range of drug discovery tasks such as molecular generation, virtual screening, lead optimization, drug property optimization, molecular dynamics simulation, accurate binding energy prediction and others. We have applied our tools successfully to discover and design potent drug candidates for various targets.
Members of our team have the experience of advancing designed molecules into clinical trials. More recently, we discovered a series of potent compounds for different orphan receptors. These compounds could result in "me-only" drug candidates.

Publication

Time

Dissertation

Periodical

Link

2024

Computational drug development for membrane protein targets

Nature Biotechnology

https://doi.org/10.1038/s41587-023-01987-2

2023

Will the hype of automated drug discovery finally be realized?

Expert Opinion on Drug Discovery

https://doi.org/10.1080/17460441.2023.2293157

2023

Celastrol Combats Methicillin-Resistant Staphylococcus aureus by Targeting Δ1-Pyrroline-5-Carboxylate Dehydrogenase

Advanced Science

https://doi.org/10.1002/advs.202302459

2021

MolADI: A Web Server for Automatic Analysis of Protein–Small Molecule Dynamic Interactions

Molecules

https://doi.org/10.3390/molecules26154625

2021

Rutin, a Natural Inhibitor of IGPD Protein, Inhibits the Formation of Biofilm in Staphylococcus xylosus ATCC700404 in vitro and in vivo

Frontiers in Pharmacology

https://doi.org/10.3389/fphar.2021.728354

2020

Clinical HDAC Inhibitors are Effective Drugs to Prevent the Entry of SARS-CoV2

ACS Pharmacology & Translational Science

https://doi.org/10.1021/acsptsci.0c00163

2020

Enhancing the Signaling of GPCRs via Orthosteric Ions

ACS Central Science

https://doi.org/10.1021/acscentsci.9b01247

2019

Advancing Drug Discovery via Artificial Intelligence

Trends in Pharmacological Sciences

https://doi.org/10.1016/j.tips.2019.06.004

2019

New binding sites, new opportunities for GPCR drug discovery

Trends in Biochemical Sciences

https://doi.org/10.1016/j.tibs.2018.11.011

2019

Computational modeling of the olfactory receptor Olfr73 suggests a molecular basis for low potency of olfactory receptor-activating compounds

Communications Biology

https://doi.org/10.1038/s42003-019-0384-8

2018

Exploring a new ligand binding site of G protein-coupled receptors

Chemical Science

https://doi.org/10.1039/C8SC01680A

2017

Implementing WebGL and HTML5 in Macromolecular Visualization and Modern Computer-Aided Drug Design

Trends in Biotechnology

https://doi.org/10.1016/j.tibtech.2017.03.009

2017

Using PyMOL as a platform for computational drug design

Computational Molecular Science

https://doi.org/10.1002/wcms.1303

Resolving membrane protein structures in real lipids

Membrane proteins

Membrane proteins are important drug targets which include G protein-coupled receptors (GPCRs), ion channels, transporters and others. Our team has close collaborations with leading scientist in the area of structural biology. However, most of current membrane protein structures were resolved at detergent or artificial lipid environments which are totally different from their physiological conditions. This in return result in losing the physiological functions of target membrane protein. Such structures will increase the cost the of structure-based drug discovery noticeably.

AlphaMol

Our team has developed a new pipeline which can resolve the membrane protein structures at real lipid environments. With such functional structures, we can design drug molecules in a more accurate way. Moreover, excellent cryoEM facilities are accessible in both China and Switzerland.

Publication

Time

Dissertation

Periodical

Link

2023

Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42

Nat Commun

https://doi.org/10.1038/s41467-023-39218-6

2023

Cryo-EM structure of human heptameric pannexin 2 channel

Nature Communications

https://doi.org/10.1038/s41467-023-36861-x

2021

Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers

Nature Communications

https://doi.org/10.1038/s41467-021-21016-7

2016

A Gating Mechanism of the Serotonin 5-HT3 Receptor

Structure

https://doi.org/10.1016/j.str.2016.03.019

2015

The Structure of the Mouse Serotonin 5-HT3 Receptor in Lipid Vesicles

Structure

https://doi.org/10.1016/j.str.2015.11.004

2014

X-ray structure of the mouse serotonin 5-HT3 receptor

Nature

https://doi.org/10.1038/nature13552

2014

Molecular and dimensional profiling of highly purified extracellular vesicles by fluorescence fluctuation spectroscopy

Analytical Chemistry

https://doi.org/10.1021/ac501801m

2011

Overcoming barriers to membrane protein structure determination

Nature Biotechnology

https://doi.org/10.1038/nbt.1833

New computational algorithm development

AlphaMol

Our team has developed an absolute binding energy prediction tool, which is known as AlphaE. With the new algorithm of AlphaE, we can predict accurately the binding activity of a compound. The RMSE (root-mean-square-energy) is as low as 1 kcal/mol in comparison with experimental data. AlphaE also overcomes many difficulties in currently available tools such as: (1) predictions are not reliable when the molecule changes too much; (2) calculations cannot be performed if molecules bind to different pockets; (3) predictions need large amount of CPU and GPU resources.
Furthermore, AlphaMol also developed many new computational algorithm and tools to predict the physical properties and drug-likeness of molecules. These tools demonstrated perfect correlations with experimental data, of which the R2 is up to 0.99.