Abstract
Bioisosteric replacement is a powerful tool for modulating the drug-like properties, toxicity, and chemical space of experimental therapeutics. In this review, we focus on selected cases where bioisosteric replacement and scaffold hopping have been used in the development of new anti-HIV-1 therapeutics. Moreover, we cover field-based, computational methodologies for bioisosteric replacement, using studies from our group as an example. It is our hope that this review will serve to highlight the utility and potential of bioisosteric replacement in the continuing search for new and improved anti-HIV drugs.
Highlights
The design and development of a lead compound into a drug is a laborious and often costly process, with most candidates failing due to metabolism and pharmacokinetics issues rather than potency
We focus on selected cases where bioisosteric replacement and scaffold hopping have been used in the development of new anti-HIV-1 therapeutics
The objective of the present review is to provide a broad understanding of the principle of bioisosteric replacement underlined with cases from recent applications in anti-HIV drug design and optimization
Summary
The design and development of a lead compound into a drug is a laborious and often costly process, with most candidates failing due to metabolism and pharmacokinetics issues rather than potency. Bioisosteric replacement is a strategy used by medicinal chemists to address these limitations while still retaining the potency/efficacy of the initial lead compound. The bioisosteric approach can be used for the rational modification of a lead compound towards a more attractive therapeutic agent with improved potency, selectivity, altered physical, metabolic, toxicological properties with the bonus of generating novel intellectual property (IP). The objective of the present review is to provide a broad understanding of the principle of bioisosteric replacement underlined with cases from recent applications in anti-HIV drug design and optimization. It is our hope that this review will serve to highlight the utility and potential of bioisosteric replacement in the continuing search for new and improved anti-HIV drugs
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