The conventional drug discovery process is associated with high costs, lengthy development timelines, and high failure rates

The gap

Evidence profile

Sourced from the future work and stated research gap of the source papers, classified as general, drawn from work published between 2017 and 2026, spanning 3 journals. Those papers have been cited 131 times in total.

Supporting evidence — 4 representative gaps

• Structure and dynamics in drug discovery (2024) · npj Drug Discovery. · cited 65× · doi

  enzymes, using structure-based virtual screening or molecular docking, with the test molecules chosen from libraries of compounds or analogs of known binders34. The quality of binding of each test molecule was typically deter- mined using model potential energy functions chosen to balance speed and accuracy34. Docking molecules of a virtual drug-like compound library into a target receptor structure and predicting its binding score is a major step in a structure-based drug discovery campaign, which plays a key role in any successful application7,29,35. The predicted candidate ligand sets, produced by such virtual screening, usually show useful hit rates, about 10%-40% in experimental testing36. Some novel hits may also exhibit noteworthy potencies, in the 0.1–10-μM range, for different types of targets36. Special attention has been devoted to ligand scoring functions, which are supposed to reliably select top binders and to rule out false-positive predictions. This is especially important with the growth of library size. For example, a one-in-a-million rate of false positives in a billion-compound library would result in a thousand false hits, which obviously complicates the selection of hit candidates. Another major challenge is the computation cost. With increasing library sizes, the computational time of docking itself is the main bottleneck in virtual screening processes. Nowadays, screenings on ultra-large virtual libraries that include billions of drug-like compounds are feasible, thanks to the recent availability of cloud computing and graphics processing unit (GPU) computing resources36.

  generalfuture work
  Keywords: virtual library structure screening docking drug false using based test molecules chosen libraries compounds binders
• Structure and dynamics in drug discovery (2024) · npj Drug Discovery. · cited 65× · doi

  40. Alon, A. et al. Structures of the σ2 receptor enable docking for bioactive ligand discovery. Nature 600, 759–764 (2021). 41. Gorgulla, C. et al. An open-source drug discovery platform enables 42. ultra-large virtual screens. Nature 580, 663–668 (2020). Sadybekov, A. A. et al. Synthon-based ligand discovery in virtual libraries of over 11 billion compounds. Nature 601, 452–459 (2022). Tomberg, A. & Boström, J. Can easy chemistry produce complex, diverse, and novel molecules? Drug Discov. Today 25, 2174–2181 (2020). 44. Gorgulla, C. et al. A multi-pronged approach targeting SARS-CoV-2 43. 45. proteins using ultra-large virtual screening. Iscience 24, 102021 (2021). Patel, H. et al. SAVI, in silico generation of billions of easily synthesizable compounds through expert-system type rules. Sci. data 7, 384 (2020). 65. Miao, Y. et al. Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor. Proc. Natl Acad. Sci. 113, E5675–E5684 (2016). Seitz, C. et al. Targeting tuberculosis: Novel scaffolds for inhibiting cytochrome bd oxidase. J. Chem. Inf. Model. (2024). 66. 67. Wong, C. F. & McCammon, J. A. J. Computer simulation and the design of new biological molecules. Isr. J. Chem. 27, 211–215 (1986). 68. Wong, C. F. & McCammon, J. A. Dynamics and design of enzymes 69. and inhibitors. J. Am. Chem. Soc. 108, 3830–3832 (1986). Jorgensen, W. L., Buckner, J. K., Boudon, S. & Tirado‐Rives, J. Efficient computation of absolute free energies of binding by computer simulations. Application to the methane dimer in water. J. Chem. Phys. 89, 3742–3746 (1988). 46. McCammon, J. A., Gelin, B. R. & Karplus, M. Dynamics of folded 70. Gilson, M. K., Given, J. A., Bush, B. L. & McCammon, J. A. The proteins. nature 267, 585–590 (1977). 47. Durrant, J. D. & McCammon, J. A. Molecular dynamics simulations 48. 49. 50. and drug discovery. BMC Biol. 9, 1–9 (2011). Lin, J.-H., Perryman, A. L., Schames, J. R. & McCammon, J. A. Computational drug design accommodating receptor flexibility: the relaxed complex scheme. J. Am. Chem. Soc. 124, 5632–5633 (2002). Amaro, R. E., Baron, R. & McCammon, J. A. An improved relaxed complex scheme for receptor flexibility in computer-aided drug design. J. Comput. -Aided Mol. Des. 22, 693–705 (2008). Lins, R. D. et al. Molecular dynamics studies on the HIV-1 integrase catalytic domain. Biophys. J. 76, 2999–3011 (1999). 51. Goldgur, Y. et al. Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium. Proc. Natl Acad. Sci. 95, 9150–9154 (1998). 52. Goldgur, Y. et al. Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design. Proc. Natl Acad. Sci. 96, 13040–13043 (1999). Schames, J. R. et al. Discovery of a novel binding trench in HIV integrase. J. Med. Chem. 47, 1879–1881 (2004). 53. 56. 55. 54. Hazuda, D. J. et al. A naphthyridine carboxamide provides evidence for d

  generalfuture work
  Keywords: mccammon drug design chem discovery receptor nature dynamics integrase virtual complex novel proc natl acad
• Click Chemistry in Medicinal Chemistry for Comprehensive Medicinal Chemistry III (2017) · Comprehensive Medicinal Chemistry III · cited 1× · doi

  296 298 304 305 309 309 311 314 317 318 318 318 322 322 324 324 324 324 324 324 325 1.10.1 Introduction Creating novel drug candidates with improved biological properties and diminished adverse effect for treating human disease such as AIDS and cancer is one of the most important challenges faced by contemporary medicinal chemists.1–4 Synthetic chemists and biologists initiated the process by taking a lead structure and then finding functional analogs exhibiting the preferred biological activities. Then, medicinal chemist used their experience and chemical insights to eventually choose a functional analog for further development.5,6 Conventional methods of drug discovery are now being implemented by approaches made possible by identifying the molecular processes involved in disease. In this view, drug design begins with attempting to identify a molecular target (typically a receptor or protein in the body) followed by identification of molecules that affect the function of that target. Making these lead structures without side products and purification is synthetically demanding.6,7 Click chemistry describes a set of powerful, highly reliable, and selective reactions to generate substances quickly and reliably by joining small units together through heteroatom links (C–X–C).8–10 Click chemistry in drug design has many advantages and key features of click chemistry can be summarized as follows:11 Click reactions progress quickly at low or room temperatures in compatible eco-friendly solvent medium such as water and water-miscible solvents such as THF, methanol, ethanol, DMF, and DMSO and are suitable for microscale solution-phase parallel synthesis without the need for protecting group manipulations. As a result, click chemistry enables the rapid and reliable screening of large library of functional analogs with almost complete chemo-selectivity with broad functional group tolerance.10,11 The orthogonality of the azide and alkyne functionalities to a diverse range of functional groups and reaction conditions allows the assembly of reactants decorated with diverse unprotected functionalities. The development of new methods for click synthesis is still of interest due to the importance of this function in drug discovery. Several existing methodologies such as copper and ruthenium salt catalyzed describe the regioselective formation of the 1,4-disubstituted triazole unit; efforts also have been made at developing methodologies for the exclusive formation of the 1,5-disubstituted regioisomers that are important in medicinal chemistry (Fig. 1A).12,13 The triazole product is an effective pharmacophore. The 1,2,3-triazole structural motif generated in the click reaction is much more than just a passive linker unit and is considered to be a safe bioequivalent surrogate for amide, which is a widely employed functional group in drug design.14 The 1,2,3-triazole moiety has several advantages:14 (i) Its chemical robustness is favorable for adoption in drug di

  generalfuture work
  Keywords: drug click functional chemistry triazole medicinal design group biological disease important chemists lead analogs chemical
• Integrative strategies in herbal product-based Drug discovery: from computational models to molecular insights (2026) · Beni-Suef University Journal of Basic and Applied Sciences · doi

  The conventional drug discovery process is associated with high costs, lengthy development timelines, and high failure rates. Challenges such as compound isolation, screening, and structural characterization limit the broader applications of natural products. There is a need for innovative discovery strategies that can address disease complexity at the systems level.

  generalstated research gapevidence 5/5
  Keywords: conventional drug discovery process associated high costs lengthy

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