Integrated Computational Approaches and Tools forAllosteric Drug Discovery

Abstract

Understanding molecular mechanisms underlying the complexity of allosteric regulationin proteins has attracted considerable attention in drug discovery due to the benefits and versatilityof allosteric modulators in providing desirable selectivity against protein targets while minimizingtoxicity and other side effects. The proliferation of novel computational approaches for predictingligand-protein interactions and binding using dynamic and network-centric perspectives has ledto new insights into allosteric mechanisms and facilitated computer-based discovery of allostericdrugs. Although no absolute method of experimental and in silico allosteric drug/site discoveryexists, current methods are still being improved. As such, the critical analysis and integration ofestablished approaches into robust, reproducible, and customizable computational pipelines withexperimental feedback could make allosteric drug discovery more efficient and reliable. In this article,we review computational approaches for allosteric drug discovery and discuss how these tools can beutilized to develop consensus workflows for in silico identification of allosteric sites and modulatorswith some applications to pathogen resistance and precision medicine. The emerging realization thatallosteric modulators can exploit distinct regulatory mechanisms and can provide access to targetedmodulation of protein activities could open opportunities for probing biological processes and insilico design of drug combinations with improved therapeutic indices and a broad range of activities.

Keywords: Allostery; MD-TASK; allosteric modulators; drug resistance; network analysis; precision medicine.

Figure 1

Three-dimensional mapping of variation positions for the 8 FDA-approved HIV protease inhibitors (atazanavir (ATV), darunavir (DRV), fosamprenavir (FPV), indinavir (IDV), lopinavir (LPV), nelfinavir (NFV), saquinavir (SQV), and tipranavir (TPV)) used to investigate the effects of drug resistance: Coloured cartoon representations depict the fulcrum, elbow, flap, cantilever, and interface, while the variation loci are shown as red spheres. Even though single positions are shown, some positions comprise multiple residue variations, some of which are validated drug resistance mutations (DRMs) (as per the 2017 update [114]). Figure obtained from Reference [115].

Figure 2

(A) Our proposed integrated workflow for allosteric site identification, which starts with the acquisition of a drug target and (B) different concepts and techniques from molecular simulation that can provide correlating information to discover and characterize allosteric events in proteins.

Figure 3

Our proposed integrated workflow for identifying allosteric modulators.