Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/ijms21030847
Keywords
Allostery; allosteric modulators; network analysis; MD-TASK; drug resistance; precision medicine
Funding
- National Institutes of Health Common Fund [U41HG006941]
- National Research Foundation (NRF) South Africa [105267]
- CSIR DST Interbursary Support (IBS)
- Organization for Women in Science for the Developing World (OWSD)
- Swedish International Development Cooperation Agency (SIDA)
- Kay Family Foundation [A20-0032]
- Grand Challenges Africa program [GCA/DD/rnd3/023]
- Grand Challenges Africa is a program of the African Academy of Sciences (AAS)
- Alliance for Accelerating Excellence in Science in Africa (AESA) platform, an initiative of the AAS
- Bill & Melinda Gates Foundation (BMGF)
- German Federal Ministry of Education and Research (BMBF)
- Medicines for Malaria Venture (MMV), and Drug Discovery and Development Centre of University of Cape Town (H3D)
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Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand-protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. As such, the critical analysis and integration of established approaches into robust, reproducible, and customizable computational pipelines with experimental 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 be utilized to develop consensus workflows for in silico identification of allosteric sites and modulators with some applications to pathogen resistance and precision medicine. The emerging realization that allosteric modulators can exploit distinct regulatory mechanisms and can provide access to targeted modulation of protein activities could open opportunities for probing biological processes and in silico design of drug combinations with improved therapeutic indices and a broad range of activities.
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