Developing low-cost and high-throughput methods to screen designed drug-like molecules

Medicilon's medicinal chemistry involves the application of a number of specialized disciplinary approaches all focused on the ultimate goal of drug discovery. Drug target identification and validation, rational (target-based) drug design, structural biology, computational-based drug design, methods development (chemical, biochemical and computational), and “Hit-to-lead” development are all aspects of medicinal chemistry. The techniques and approaches of chemical biology, synthetic organic chemistry, combinatorial (bio)chemistry, mechanistic enzymology, computational chemistry, chemical genomics and high-throughput screening are all used and applied by medicinal chemists towards drug discovery. Email:marketing@medicilon.com.cn web:www.medicilon.com

A nanosensor for detecting molecule characteristics includes a membrane having an opening configured to permit a charged molecule to pass but to block a protein molecule attached to a ligand connecting to the charged molecule, the opening being filled with an electrolytic solution. An electric field generator is configured to generate an electric field relative to the opening to drive the charged molecule through the opening. A sensor circuit is coupled to the electric field generator to sense current changes due to charged molecules passing into the opening. The current changes are employed to trigger a bias field increase to cause separation between the ligand and the protein to infer an interaction strength.

In accordance with the present principles, a drug-screening device is provided that employs a physical method with little to no sample preparation. The drug-screening device can provide a low-cost and high-throughput method for screening drugs. A nanopore is employed as a force sensor to detect an affinity between a drug molecule (ligand) and a targeted protein molecule (receptor). The binding affinity of the complex can be derived from measured electric signals. The application of this ultra-sensitive (e.g., for a binding energy of a few kBT (e.g., 1-10) between the ligand and the protein) screening device could greatly accelerate the process of developing new drugs, particularly for narrow screening and lead optimization.

Screening is a method for scientific experimentation used in drug discovery. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, screening permits a researcher to quickly conduct millions of chemical, genetic or pharmacological tests. Through this process one can rapidly identify active compounds, antibodies or genes which modulate a particular biomolecular pathway. The results of these experiments provide starting points for drug design and for understanding the interaction or role of a particular biochemical process in biology. Lead optimization is the process of optimizing a drug and bringing a new drug to market once a lead compound has been identified through a drug discovery process. By employing the present principles, narrow screening and lead optimization are improved by reducing the time and resources needed for these and other drug discovery processes.

In one embodiment, a method and device are provided for detecting an affinity of a drug molecule to a targeted protein molecule using a nanopore (a nanometer-sized hole in a thin membrane). The binding affinity of a complex may also be detected using multiple nanopores, a fluidic channel or multiple fluidic channels to screen drug molecules (ligands) to a targeted protein molecule (receptor). A charged carbon nanotube (CNT) is employed to determine the binding affinity; however, the CNT may be replaced with other linear and charged molecules (such as DNA or a nano-wire).

It is to be understood that the present invention will be described in terms of a given illustrative architecture having a nanopore; however, other architectures, structures, materials and process features and steps may be varied within the scope of the present invention.

It will also be understood that when an element such as a layer, region, membrane, etc. is referred to as being “on” or “over” another element, it can be directly on the other element or intervening elements may also be present. In contrast, when an element is referred to as being “directly on” or “directly over” another element, there are no intervening elements present. It will also be understood that when an element is referred to as being “connected” or “coupled” to another element, it can be directly connected or coupled to the other element or intervening elements may be present. In contrast, when an element is referred to as being “directly connected” or “directly coupled” to another element, there are no intervening elements present.