Abstract
The ability to rapidly assess the preferred conformation of key fragments in a structure “by visual inspection” is a very useful starting point in the process of drug design. With the ability to do so, one could address questions like: “How could we avoid planarity in a molecule?”, “Will a molecule change its conformational preference if we make it more or less basic?” or “How does this electronic repulsion affect the conformational preference in the system?” in timely fashion. In this paper, we describe how the conformational energy profile (CEP, plot of energy as a function of dihedral bond angle) of a fragment can be interpreted through the understanding the interplay between resonance stabilization, steric effects and electrostatic interactions. Fifty-nine biaryl and aryl carbonyl fragments present in oral drugs or which are close derivatives thereof were selected. Calculation of their CEPs using ab initio methodology allowed us to conclude the relative importance of these factors in the conformational preference of these fragments as follows: “steric repulsion > lone pair—lone pair repulsion > lone pair—fluorine repulsion > resonance stabilization” and to formulate “rules of thumb” that the practicing medicinal/organic chemist can apply when analysing molecules that contain these fragments.
Highlights
Understanding a molecule’s conformational preference [1,2,3] is critical in the practice of medicinal chemistry [4]
We report an expansion of these studies including 6, 6-biaryls, 5, 6-biaryls and aryl carbonyl fragments as structural motifs commonly used in drug discovery
We investigated the steric effects of larger alkyl groups in the 2-position of the biphenyl system (Fig 7)
Summary
Understanding a molecule’s conformational preference [1,2,3] is critical in the practice of medicinal chemistry [4]. Factors that affect a molecule’s biological activity, such as the shape, physicochemical properties and the position of key functional groups, are highly dependent on its conformation. [5] Computational methods (molecular mechanics, semi-empirical or ab initio) are often employed to identify low energy conformations and to guide compound design to optimize biological activity [6,7]. Company employee who owns company stock and receives a pension. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials
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