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Intramolecular hydrogen bonding: An opportunity for improved design in medicinal chemistry
Univ Torino, Mol Biotechnol & Hlth Sci Dept, Via Quarello 15, I-10135 Turin, Italy.ORCID iD: 0000-0002-2417-5900
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.ORCID iD: 0000-0002-4205-6040
Univ Torino, Mol Biotechnol & Hlth Sci Dept, Via Quarello 15, I-10135 Turin, Italy.
2019 (English)In: Medicinal research reviews (Print), ISSN 0198-6325, E-ISSN 1098-1128, Vol. 39, no 5, p. 1707-1729Article, review/survey (Refereed) Published
Abstract [en]

Recent literature shows that intramolecular hydrogen bond (IMHB) formation can positively impact upon the triad of permeability, solubility, and potency of drugs and candidates. IMHB modulation can be applied to compounds in any chemical space as a means for discovering drug candidates with both acceptable potency and absorption, distribution, metabolism, and excretion-Tox profiles. Integrating IMHB formation in design of drugs is, therefore, an exciting and timely challenge for modern medicinal chemistry. In this review, we first provide some background about IMHBs from the medicinal chemist's point of view and highlight some IMHB-associated misconceptions. Second, we propose a classification of IMHBs for drug discovery purposes, review the most common in silico tactics to include IMHBs in lead optimization and list some experimental physicochemical descriptors, which quantify the propensity of compounds to form IMHBs. By focusing on the compounds size and the number of IMHBs that can potentially be formed, we also outline the major difficulties encountered when designing compounds based on the inclusion of IMHBs. Finally, we discuss recent case studies illustrating the application of IMHB to optimize cell permeability and physicochemical properties of small molecules, cyclic peptides and macrocycles.

Place, publisher, year, edition, pages
2019. Vol. 39, no 5, p. 1707-1729
Keywords [en]
cyclic peptides, drug design, hydrogen bond, intramolecular, macrocycles
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-393604DOI: 10.1002/med.21562ISI: 000479271600006PubMedID: 30659634OAI: oai:DiVA.org:uu-393604DiVA, id: diva2:1354422
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved

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