Emerging Computational Methods for the Rational Discovery of Allosteric Drugs

Abstract

Allosteric drug development holds promise for delivering medicines that are more selective and less toxic than those that target orthosteric sites. To date, the discovery of allosteric binding sites and lead compounds has been mostly serendipitous, achieved through high-throughput screening. Over the past decade, structural data has become more readily available for larger protein systems and more membrane protein classes (e.g., GPCRs and ion channels), which are common allosteric drug targets. In parallel, improved simulation methods now provide better atomistic understanding of the protein dynamics and cooperative motions that are critical to allosteric mechanisms. As a result of these advances, the field of predictive allosteric drug development is now on the cusp of a new era of rational structure-based computational methods. Here, we review algorithms that predict allosteric sites based on sequence data and molecular dynamics simulations, describe tools that assess the druggability of these pockets, and discuss how Markov state models and topology analyses provide insight into the relationship between protein dynamics and allosteric drug binding. In each section, we first provide an overview of the various method classes before describing relevant algorithms and software packages.

Chirality-induced spin polarization places symmetry constraints on biomolecular interactions

“…Rather, it is an additional contribution to the forces acting at short distance that can enhance the affinity and are intrinsically enantioselective. It has long been known that the current physical models used to describe the interaction between biological molecules do not properly account for the enantioselectivity and binding energies in biorecognition (2)(3)(4)(5). In the past, this gap was filled using empirically based methods (34).…”

“…Biorecognition, which is based on noncovalent interactions between molecules, retains mysteries, and its calculation evades first principles theory (2, 3). This failure suggests that some essential features are not included in our current description of these interactions (4,5). In this study, we show that charge polarization, which occurs in any biorecognition event, is accompanied by spin polarization for chiral molecules, an effect that is missing in most treatments.…”

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

“…Admittedly, it is hard to stay on top of a still rapidly developing synthetic methodology and move to systems of biological complexity at the same time. Some opinions signify that we have a complete array of methods available with which to probe and investigate living systems, for example the use of computational methods applied to rational drug design [35].…”

“…Admittedly, it is hard to stay on top of a still rapidly developing synthetic methodology and move to systems of biological complexity at the same time. Some opinions signify that we have a complete array of methods available with which to probe and investigate living systems, for example the use of computational methods applied to rational drug design [35].Molecular metaphors can have a broad range of applications, from synthetic organic chemistry to nanotechnology platforms [36] and including biomaterials [37]. Consequently, this review provides a valuable contribution to the interest of drug discovery and molecular imaging groups.…”

Untitled

“…For these proteins, their dynamic nature plays an essential role due to fundamentally exist as conformational ensembles. A similar example could be allosteric proteins for which protein flexibility have a great role been exploited to drug design [11,12].…”