Re earch & Development

Transforming Hope into Cure

The Drug Discovery and IND Application Process: Navigating the Path to Innovation

The drug discovery process represents the initial and pivotal phase in the development of

pharmaceutical and biologic products. This intricate journey, addressing scientific rigor and

regulatory compliance, paves the way for groundbreaking medications to reach patients in need. From

the moment a potential therapeutic compound is identified to the submission of an Investigational

New Drug (IND) application to regulatory authorities, the drug discovery process unfolds as a

methodically orchestrated sequence of events.

Compound

Collections

Clinical

Candidate

Iterate

DRUG
DISCOVERY
CYCLE

Primary Assays high through-put, in vitro

Secondary Assays counter screen, bioavailability toxicity, metabolism, etc.

Structural Characterization

of Protein-Ligand

complex

Design

Chemical

Synthesis

Lead

compounds

and

SAR

Drug Discovery and Optimization: The Inception of Innovation

Discovery commences with the identification of a promising compound that possesses

therapeutic potential. This phase, often referred to as drug discovery, involves extensive research

and screening, aiming to pinpoint compounds that exhibit the desired pharmacological activity.

Medicinal chemistry and biological screening play crucial roles in fine-tuning these compounds

to optimize their therapeutic properties.

At CureScience, the traditional drug discovery and development process has been refined to
encompass the term translational medicine and to focus more on a personalized approach to drug
discovery. Translational research plays a pivotal role in bridging the gap between fundamental
scientific breakthroughs and their practical application in clinical and community healthcare
settings. This transition from laboratory discoveries to real-world patient care, encompassing the
development of novel drugs, medical devices, and healthcare products, as well as promising
treatment modalities, is commonly referred to as the journey from the "bench-side to bedside".

Successful translational drug discovery necessitates collaboration between clinical and
pharmacological research, highlighting the critical role that academia plays in identifying potential

drug targets and in the design and development of pharmaceuticals. The translational medicine

process requires recurring interactive feedback between different disciplines for successful new

drug development.

During this stage, a comprehensive understanding of the compound's pharmacological characteristics

is imperative. Scientists assess the compound's efficacy in vitro (in a laboratory setting) and in

vivo (in living organisms). They also delve into the compound's toxicological profile to identify any

potential adverse effects. This early phase is resource-intensive, with substantial investments in

research and development.

Target Identification
Once the program has been agreed upon, the next part of this phase is the identification of
a target. Target identification involves the identification of a gene or protein (which
serves as a potential therapeutic agent) that plays a crucial role in a disease. Subsequently,
scientists and researchers document the therapeutic attributes of this target. Effective drug

targets must possess qualities like efficacy, safety, usability, and the ability to meet
clinical and commercial criteria.

Due to the escalating number of newly identified targets and the resulting surge in datarequiring analysis, the imperative arises to devise innovative approaches capable ofmanaging the burgeoning expenses associated with research and development (R&D),particularly within the field of pharmacology. In pursuit of this objective, the essentialintegration of computational chemistry and bioinformatics has become indispensable.

Target Validation

Target validation is a pivotal stage in drug development, just like target identification. To validate these targets, researchers employ contemporary tools and methodologies, including disease association studies, analysis of bioactive molecules, utilization of cell-based models, investigation of protein interactions, analysis of signaling pathways, functional evaluation of genes, in vitro genetic manipulation, deployment of antibodies, and chemical genomics techniques. It serves the crucial purpose of confirming that targeting the identified target holds promise for therapeutic benefits. Without successful validation, a target cannot progress further in the drug development pipeline.

Screening Methodology
During hit to lead discovery, screening methodology must be developed to determine
what compounds are potential candidates for further lead optimization. There are
numerous methods for identifying potential lead candidates. For example, in vitro and in
vivo discovery approaches with high sample throughput and high-content analysis to
characterize biological responses are often used in a variety of scenarios. Herewith are
general examples of assay methods:

High-throughput screening (HTS) employs automated equipment for the evaluation of thousands to millions of samples for their biological activity.
Originally pioneered by pharmaceutical companies, HTS was developed to identify chemical compounds with potential therapeutic properties.
Biochemical assays employ protein, enzyme-based, or receptor assays, often utilizing a purified target. These assays commonly utilize techniques like scintillation proximity assay (SPA), radiometric methods, and colorimetric or fluorescence detection.
Cell health screening assays utilize high-throughput techniques to investigate the impact of drug candidates on cellular well-being. Comparative analysis can be conducted by simultaneously examining other aspects of cell health, such as apoptosis and autophagy.
Additional screening assay methods employed in drug discovery encompass:
- Immunoassays (IAs)
- Fibrosis assays
- Ion channel screening
- Enzyme-linked immunosorbent assay (ELISA)

Preclinical Studies: The Scientific Prelude
Preclinical studies are the bridge between drug discovery and clinical trials. These investigations
involve a comprehensive examination of the compound's performance in various biological
systems. Researchers evaluate its pharmacodynamics, pharmacokinetics, and toxicology. The
goal is to establish a solid foundation for the compound's safety and efficacy.

In preclinical studies, the focus is on gathering sufficient evidence to support the transition to
human trials. The compound must meet specific performance criteria established by the
sponsoring organization. The rigorous scrutiny ensures that only the most promising candidates
advance to the next phase of development.

Investigational New Drug (IND) Application: A Regulatory Milestone
Once a compound demonstrates promise and meets predetermined performance benchmarks, the
journey enters a pivotal phase - the submission of an Investigational New Drug (IND)
application. This application is a comprehensive dossier containing scientific, manufacturing,
and safety data.

The IND application is filed with the regulatory authority, such as the U.S. Food and Drug
Administration (FDA). This milestone triggers an exhaustive review process, during which the
FDA assesses the compound's suitability for human trials. Regulatory authorities scrutinize the
IND to ensure that the compound is manufactured in accordance with current good
manufacturing practice (CGMP) standards. The goal is to ascertain the safety and integrity of the
investigational product.

Furthermore, the FDA reviews the proposed study protocols, outlining the design and conduct of
Phase I clinical trials. The regulatory review culminates in the approval of the IND, granting
permission to initiate human trials and marking a significant milestone in the drug development
journey.

The drug discovery process (a 7 – 10 year journey to this point), leading to the submission of an
IND application, is a multifaceted endeavor marked by scientific rigor, stringent regulatory
oversight, and considerable investment. The successful navigation of this process hinges on the
convergence of scientific innovation, meticulous evaluation, and unwavering commitment to
ensuring the safety and efficacy of emerging pharmaceutical and biologic products. It represents
the inception of a pharmaceutical product's journey toward reaching the patients whose well-
being depends on the fruits of this laborious but essential endeavor.

Hit to Lead Generation
Once valid targets are identified, it is necessary to apply efficient tools for the screening
of compounds against the target or set of targets.

Computer-aided drug design (CADD) represents a contemporary computational
methodology integral to the drug discovery process for identifying and cultivating
potential lead compounds. CADD encompasses various facets, including computational

chemistry, molecular modeling, molecular design, and rational drug design. This
approach is employed for the optimization of identified lead candidates, gaining
widespread recognition and adoption in both academic and pharmaceutical domains. The
CADD methodology can be described in four distinct phases:

1. Screening a library of small molecules against the target through virtual screening
(VS) protocols to pinpoint hits/leads.
2. Evaluating the specificity of selected hits from VS by employing molecular
docking within the active sites of other known targets.
3. Predicting the ADMET (Absorption, Distribution, Metabolism, Excretion, and
Toxicity) properties of the chosen hits through in silico techniques, designating
promising compounds as leads.
4. Facilitating the optimization of leads by crafting improved molecules for
synthesis and subsequent testing.

Computer-aided drug design (CADD) techniques are categorized into two types:
structure-based drug design (SBDD) and ligand-based drug design (LBDD). The
categorization is based on the availability of the target protein's 3D structure.

Structure-based drug design (SBDD):

Requires the 3D information of the target to be known
Relies exclusively on prior knowledge of a protein structure to derive novel ligands
The abundance of 3D structures for target proteins has greatly expedited the procedures within Structure-Based Drug Design (SBDD).

Ligand-based drug design (LBDD):

In the absence of 3D receptor information, this approach is used and depends on our understanding of molecules that interact with the biological target of interest.
Employed in cases where the 3D structure of the target is undisclosed
Leverages data concerning the molecules that interact with the target of interest

Re earch & Development

Transforming Hope into Cure

The Drug Discovery and IND Application Process: Navigating the Path to Innovation

DRUG DISCOVERY CYCLE

Drug Discovery and Optimization: The Inception of Innovation

Discovery commences with the identification of a promising compound that possesses

therapeutic potential. This phase, often referred to as drug discovery, involves extensive research

and screening, aiming to pinpoint compounds that exhibit the desired pharmacological activity.

Medicinal chemistry and biological screening play crucial roles in fine-tuning these compounds

to optimize their therapeutic properties.

Transforming Hope into Cure

DRUG
DISCOVERY
CYCLE