Requirements for a lead compound to become a clinical candidate

A drug candidate suitable for clinical testing is expected to bind selectively to the receptor site on the target, to elicit the desired functional response of the target molecule, and to have adequate bioavailability and biodistribution to elicit the desired responses in animals and humans; it must also pass formal toxicity evaluation in animals. The path from lead to clinical drug candidate represents the most idiosyncratic segment of drug discovery and development. Each program is unique and setbacks are common, making it difficult to predict accurately the duration or costs of this segment. Because of incidents of unpredicted human toxicity seen in recent years, the regulatory agencies and public demands for safety of new drug candidates have become very strict, and safety issues are dominant when identifying a clinical drug candidate

Single Cycle Structure-Based Humanization of an Anti-Nerve Growth Factor Therapeutic Antibody

Most forms of chronic pain are inadequately treated by present therapeutic options. Compelling evidence has accumulated, demonstrating that Nerve Growth Factor (NGF) is a key modulator of inflammatory and nociceptive responses, and is a promising target for the treatment of human pathologies linked to chronic and inflammatory pain. There is therefore a growing interest in the development of therapeutic molecules antagonising the NGF pathway and its nociceptor sensitization actions, among which function-blocking anti-NGF antibodies are particularly relevant candidates

Polypeptide and Protein Modeling for Drug Design

The main pathways involved in pain processing have been known for some time, but the precise microcircuitry remains surprisingly unclear. This has allowed very different theories of pain processing to persist. Specificity theory holds that pain is qualitatively distinct from other somatosensory percepts and that the underlying circuitry is arranged as labeled lines. Gate control theory holds that all inputs converge and that it is the level of activation in unspecialized neurons that code for pain. The truth lies somewhere in between. The dorsal horn of the spinal cord, which corresponds to the first synaptic relay point, comprises a diverse set of interneurons whose connectivity is only partially worked out. This lack of data has hindered network-level modeling, but this also presents an opportunity for modeling to help guide future experiments