Editing Drug design (section)

=== Drug discovery ===

====Phenotypic drug discovery====

[[Classical pharmacology|Phenotypic drug discovery]] is a traditional drug discovery method, also known as forward pharmacology or classical pharmacology. It uses the process of phenotypic screening on collections of synthetic small molecules, natural products, or extracts within chemical libraries to pinpoint substances exhibiting beneficial therapeutic effects. This method is to first discover the in vivo or in vitro functional activity of drugs (such as extract drugs or natural products), and then perform target identification. Phenotypic discovery uses a practical and target-independent approach to generate initial leads, aiming to discover pharmacologically active compounds and therapeutics that operate through novel drug mechanisms.<ref>{{cite journal | vauthors = Swinney DC, Lee JA | title = Recent advances in phenotypic drug discovery | journal = F1000Research | volume = 9 | pages = F1000 Faculty Rev–944 | date = 2020 | pmid = 32850117 | pmc = 7431967 | doi = 10.12688/f1000research.25813.1 | doi-access = free }}</ref> This method allows the exploration of disease phenotypes to find potential treatments for conditions with unknown, complex, or multifactorial origins, where the understanding of molecular targets is insufficient for effective intervention.<ref>{{cite journal | vauthors = Moffat JG, Vincent F, Lee JA, Eder J, Prunotto M | title = Opportunities and challenges in phenotypic drug discovery: an industry perspective | journal = Nature Reviews. Drug Discovery | volume = 16 | issue = 8 | pages = 531–543 | date = August 2017 | pmid = 28685762 | doi = 10.1038/nrd.2017.111 | s2cid = 6180139 | doi-access = free }}</ref>

====Rational drug discovery====

Rational drug design (also called [[reverse pharmacology]]) begins with a hypothesis that modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be selected as a drug target, two essential pieces of information are required.  The first is evidence that modulation of the target will be disease modifying. This knowledge may come from, for example, disease linkage studies that show an association between mutations in the biological target and certain disease states.<ref>{{cite book | title = Introduction to Biological and Small Molecule Drug Research and Development: theory and case studies | vauthors = Ganellin CR, Jefferis R, Roberts SM | year = 2013 | publisher = Elsevier | chapter = The small molecule drug discovery process — from target selection to candidate selection | chapter-url = https://books.google.com/books?id=342JY314Fl4C&q=target+validation+disease+linkage&pg=PA83 | isbn = 9780123971760}}</ref> The second is that the target is capable of binding to a small molecule and that its activity can be modulated by the small molecule.<ref name="Yuan_2013">{{cite journal | vauthors = Yuan Y, Pei J, Lai L | title = Binding site detection and druggability prediction of protein targets for structure-based drug design | journal = Current Pharmaceutical Design | volume = 19 | issue = 12 | pages = 2326–2333 | date = Dec 2013 | pmid = 23082974 | doi = 10.2174/1381612811319120019 }}</ref>

Once a suitable target has been identified, the target is normally [[molecular cloning|cloned]] and [[protein production|produced]] and [[protein purification|purified]]. The purified protein is then used to establish a [[Drug discovery#Screening and design|screening assay]]. In addition, the three-dimensional structure of the target may be determined.

The search for small molecules that bind to the target is begun by screening libraries of potential drug compounds. This may be done by using the screening assay (a "wet screen"). In addition, if the structure of the target is available, a [[virtual screening|virtual screen]] may be performed of candidate drugs. Ideally, the candidate drug compounds should be "[[druglikeness|drug-like]]", that is they should possess properties that are predicted to lead to [[oral bioavailability]], adequate chemical and metabolic stability, and minimal toxic effects.<ref>{{cite journal | vauthors = Rishton GM | title = Nonleadlikeness and leadlikeness in biochemical screening | journal = Drug Discovery Today | volume = 8 | issue = 2 | pages = 86–96 | date = January 2003 | pmid = 12565011 | doi = 10.1016/s1359644602025722 }}</ref> Several methods are available to estimate druglikeness such as [[Lipinski's Rule of Five]] and a range of scoring methods such as [[lipophilic efficiency]].<ref>{{cite book | title = The Practice of Medicinal Chemistry | editor = Wermuth CG | vauthors = Hopkins AL | chapter = Chapter 25: Pharmacological space | pages = 521–527 | chapter-url = https://books.google.com/books?id=Qmt1_DQkCpEC&q=druggability+Lipinski%27s+Rule+of+Five+lipophilic+efficiency&pg=PA527 | isbn = 978-0-12-374194-3 | publisher = Academic Press | edition = 3 | year = 2011 }}</ref> Several methods for predicting drug metabolism have also been proposed in the scientific literature.<ref>{{cite book | title = Drug Metabolism Prediction | vauthors = Kirchmair J | isbn = 978-3-527-67301-8 | year = 2014 | publisher = Wiley-VCH | volume = 63 | series = Wiley's Methods and Principles in Medicinal Chemistry }}</ref>

Due to the large number of drug properties that must be simultaneously optimized during the design process, [[multi-objective optimization]] techniques are sometimes employed.<ref>{{cite journal | vauthors = Nicolaou CA, Brown N | title = Multi-objective optimization methods in drug design | journal = Drug Discovery Today: Technologies | volume = 10 | issue = 3 | pages = e427–e435 | date = September 2013 | pmid = 24050140 | doi = 10.1016/j.ddtec.2013.02.001 }}</ref>  Finally because of the limitations in the current methods for prediction of activity, drug design is still very much reliant on [[Serendipity#Pharmacology|serendipity]]<ref>{{cite journal | vauthors = Ban TA | title = The role of serendipity in drug discovery | journal = Dialogues in Clinical Neuroscience | volume = 8 | issue = 3 | pages = 335–344 | year = 2006 | pmid = 17117615 | pmc = 3181823 | doi = 10.31887/DCNS.2006.8.3/tban }}</ref> and [[bounded rationality]].<ref>{{cite journal | title = Bounded Rationality and the Search for Organizational Architecture: An Evolutionary Perspective on the Design of Organizations and Their Evolvability | vauthors = Ethiraj SK, Levinthal D | journal = Administrative Science Quarterly | volume = 49 | issue = 3 | date = Sep 2004 | pages = 404–437 | publisher = Sage Publications, Inc. on behalf of the Johnson Graduate School of Management, Cornell University | doi = 10.2307/4131441 | jstor = 4131441 | ssrn = 604123 | s2cid = 142910916 | url = https://repository.upenn.edu/mgmt_papers/76 }}</ref>