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Approaches for Identification and Validation of Antimicrobial Compounds of Plant Origin: A Long Way from the Field to the Market
Published in Mahendra Rai, Chistiane M. Feitosa, Eco-Friendly Biobased Products Used in Microbial Diseases, 2022
Lívia Maria Batista Vilela, Carlos André dos Santos-Silva, Ricardo Salas Roldan-Filho, Pollyanna Michelle da Silva, Marx de Oliveira Lima, José Rafael da Silva Araújo, Wilson Dias de Oliveira, Suyane de Deus e Melo, Madson Allan de Luna Aragão, Thiago Henrique Napoleão, Patrícia Maria Guedes Paiva, Ana Christina Brasileiro-Vidal, Ana Maria Benko-Iseppon
However, it is noteworthy that it is a process with retroactive takes, where resumes from previous phases are more common than one may imagine. When a potential candidate arrives in the clinical tests phase and presents undesirable characteristics, it is advisable to return to the previous phases to remodel the molecules and find plausible alternatives. Choosing the right biological target or a combination of targets is one of the main tasks for any successful drug discovery project. All subsequent efforts, whether small molecule identification, compound optimization, pharmacokinetic studies or a clinical trial, will be as effective as the initial decision to choose one target or another (Blaney 2012; Faust et al. 2021).
Drug Design, Synthesis, and Development
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Understanding organic reaction mechanisms and the step-by-step processes by which molecules can be combined and altered enables chemists to design novel compounds. This is of fundamental importance to drug discovery because new drug molecules can be rationally designed to interact with a biological target associated with a disease and therefore have a biological effect that improves the condition of the patient. Subtle modification of molecular structures and lead compound optimisation can be done by implementing techniques in organic synthesis to yield the best possible drug properties of a lead compound. A key example of where this is important is asymmetric synthesis, where a stereospecific drug-target interaction is required, which could otherwise lead to side effects; note the case of thalidomide. While it is imperative to synthesise drugs with the least possible side effects, it is also essential to ensure the purity of drugs. This is the role of the analytical chemist, who has the important occupation of screening for and eliminating contaminants. Analytical techniques have improved greatly in modern times; contaminants can be traced below nano-gram levels, and methods such as spectroscopic techniques can be used to characterise the contaminants. As technologies advance in the future, medicinal chemists will be well equipped to manage the challenges that are presented to the field of medicine in the coming decades.
Key Concepts in Assay Development, Screening and the Properties of Lead and Candidate Compounds
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
It is important to ensure that a common set of definitions is used in the drug discovery value chain so that all stakeholders have a common basis for expectations when evaluating compounds. Commonly accepted definitions in the pre-clinical stages are: Biological Target: A macromolecule with known function, disease association and involvement, and ideally 3-dimensional structure.Validated Hit: A molecule with robust dose-response activity in an assay that utilises the target protein with confirmed structure and preliminary SAR information.Lead Compound: A representative compound series which satisfies predefined criteria (see Table 1) for progression to Lead-to-Candidate optimisation.Candidate: A representative compound that satisfies predefined criteria (see Table 2) for progression to subsequent IND submission.
Smart design of patient-centric long-acting products: from preclinical to marketed pipeline trends and opportunities
Published in Expert Opinion on Drug Delivery, 2022
Céline Bassand, Alessia Villois, Lucas Gianola, Grit Laue, Farshad Ramazani, Bernd Riebesehl, Manuel Sanchez-Felix, Kurt Sedo, Thomas Ullrich, Marieta Duvnjak Romic
The design of LAIs does not follow the same principles as oral products. The requirements for the DS are replaced by different criteria: low solubility in the injection site’s compartment, good compatibility with an injectable medium or depot carrier, or functional groups that can serve as anchor points for prodrug generation (Figure 5(a)). Optimization for extremely high potency against a specific biological target or pathway is additionally important because of maximum dose limitations. The main concerns for the DP are the abilities to administer the highest quantity of DS with the minimum volume, and to appropriately control the DS release, to offer patients longest dosing intervals possible (Figure 5(a)). Another crucial parameter is the appropriate choice of excipients, as they can have a significant impact on drug release, immune response, and tolerability [2,51,52]. Moreover, their safe exposure limits need to be considered [2,51,52].
The latest automated docking technologies for novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
The design of a drug that specifically binds to a relevant biological target is the common task of medicinal chemists. However, the development of multitarget drugs for the treatment of diseases is a more efficient way to reduce drug resistance and toxicity. Multitarget drug design is an endeavor that uses experimentally validated structural protein-ligand information in PDB, and computational methods, such as shape screening, pharmacophore screening, and reverse (or inverse) molecular docking [37,38], where the binding of an active compound is explored against multiple clinically relevant target proteins (Figure 1). In this sense, a reverse docking protocol can be employed to identify novel protein targets for a drug. As a result, a novel mechanism of action or side effect for the drug can be proposed. Reverse docking can be also used to discover innovative treatments using abandoned and existing molecules/drugs (drug repositioning and drug rescue approaches) [39].
Entering the era of computationally driven drug development
Published in Drug Metabolism Reviews, 2020
Neha Maharao, Victor Antontsev, Matthew Wright, Jyotika Varshney
The PK component provides the time course of measured drug concentrations usually in plasma (Cp) and PK models can be used to model the disposition kinetics. A suitable mathematical function describes the relationship between drug concentration in plasma and the tissue of interest (Ce, biophase concentration) (Jusko et al. 1995; Wright et al. 2011). The biophase drug levels are believed to be the driving force for the pharmacological effects (Mager et al. 2003). Drug molecules at the site of action interact with the biological target, usually a receptor or an enzyme. The biophase sensor process encompasses the kinetics of reversible or irreversible binding and dissociation of drug–receptor or drug–enzyme complexes (Jusko et al. 1995; Wright et al. 2011). These drug–biological target interactions may directly or indirectly increase or reduce the production (kin) or dissipation (kout) of endogenous substances, which may represent the desired PD effect (Jusko et al. 1995; Mager et al. 2003). Often, however, the altered levels of endogenous substrates trigger a further dynamic transduction process ultimately leading to an acute or long-lasting pharmacological effect (E) (Mager et al. 2003). PK/PD modeling enables mathematical characterization of the relationship between PK and PD and hence is applied to all stages of drug development.