title: Activity cliffs in drug discovery: Dr Jekyll or Mr Hyde?
abstract: The impact activity cliffs have on drug discovery is double-edged. For instance, whereas medicinal chemists can take advantage of regions in chemical space rich in activity cliffs, QSAR practitioners need to escape from such regions. The influence of activity cliffs in medicinal chemistry applications is extensively documented. However, the 'dark side' of activity cliffs (i.e. their detrimental effect on the development of predictive machine learning algorithms) has been understudied. Similarly, limited amounts of work have been devoted to propose potential solutions to the drawbacks of activity cliffs in similarity-based approaches. In this review, the duality of activity cliffs in medicinal chemistry and computational approaches is addressed, with emphasis on the rationale and potential solutions for handling the 'ugly face' of activity cliffs.
authors.affiliation: CIQ, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal; REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal; Centro de Estudios de Química Aplicada (CEQA), Faculty of Chemistry and Pharmacy, Central University of Las Villas, Santa Clara 54830, Cuba; Molecular Simulation and Drug Design Group, Centro de Bioactivos Químicos (CBQ), Central University of Las Villas, Santa Clara 54830, Cuba. Electronic address: gmailkelcm@yahoo.es.
authors.forename: Maykel
authors.initials: M
authors.lastname: Cruz-Monteagudo
authors.affiliation: Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
authors.affiliation: Molecular Simulation and Drug Design Group, Centro de Bioactivos Químicos (CBQ), Central University of Las Villas, Santa Clara 54830, Cuba.
authors.forename: Yunierkis
authors.initials: Y
authors.lastname: Pérez-Castillo
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'Aldo Moro', Via Orabona 4, 70125 Bari, Italy.
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.affiliation: REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.
authors.forename: M Natália D S
authors.initials: MN
authors.lastname: Cordeiro
authors.affiliation: CIQ, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
mesh_terms: D000465:Algorithms; D002626:Chemistry, Pharmaceutical / Q000379:methods; D019295:Computational Biology / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D013329:Structure-Activity Relationship