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Biological and Medicinal Chemistry

Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

Shunzhou Wan, Agastya Bhati, Alex Wade, Dario Alfe, Peter Coveney

Although researchers have been working tirelessly since the COVID

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Theoretical and Computational Chemistry

MoleGuLAR: Molecule Generation using Reinforcement Learning with Alternating Rewards

Manan Goel, Shampa Raghunathan, Siddhartha Laghuvarapu, U. Deva Priyakumar

Design of new inhibitors for novel targets is a very important problem especially in the current scenario with the world being plagued by COVID

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Theoretical and Computational Chemistry

Cosolvent and Dynamic Effects in Binding Pocket Search by Docking Simulations

P. Bernát Szabó, Francesc Sabanés Zariquiey, Juan José Nogueira

Ligand counts are reported separately for each cosolvent utilised to obtain the protein conformation to which the ligand binds and the apo crystal structure. For the definition of the pocket numbering see Figure 7 and Table 2. pocket binding energy criterion energy gap criterion water benzene phenol crystallized water benzene phenol crystallized 1 56 8 99 2 31 3 9 1 2 9 67 22 1 25 13 11 0 3 0 11 4 3 0 3 2 1 4 4 29 9 0 3 10 2 0 5 29 2 5 0 19 0 0 0 6 0 6 0 0 1 7 0 1 7 0 4 0 0 0 5 0 0 8 0 0 0 0 4 2 0 0 9

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Theoretical and Computational Chemistry

Combination of pose and rank consensus in docking-based virtual screening: the best of both worlds

Valeria Scardino, Mariela Bollini, Claudio Cavasotto

This last option showed the best performance in almost every target evaluated, with the exception of two cases (NRAM and HMDH) where the difference was minimal. 9 Table 6: Evolution of the EF values for different strategies as molecular selection criteria are added: pose consensus alone using 4 MPs; Option D (2 MPs top 5% - 3MPs top 10% - 4MPs top 20%; Option E or PRC (Option D with an ECR top1.5% threshold). The hit rate (HR) represents the probability of finding a ligand within the selected molecules. Receptor 4 MPs Option D Option E (PRC) A/Sa EF A/Sa EF A/Sa EF HR KITH 17/83 4.7 15/23 14.8 13/15 19.7 0.87 PA2GA 9 /81 4.7 16/30 22.4 12/16 31.5 0.75 FA7 9 /100 3.2 64/73 30.7 44/45 34.3 0.98 HXK4 6/135 1.7 15/45 12.9 9

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Theoretical and Computational Chemistry

Fast and Automated Identification of Reactions with Low Barriers: The Decomposition of 3-Hydroperoxypropanal

Maria Harris Rasmussen, Mads Madsen, Jan H. Jensen

The imaginary frequency is ≈100 cm−1 R35 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1O:2 C:3 H:6 H:7 C:5 H:9 H:10O:8 H:4 O:11 H:12+ R36 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1O:2 C:3 H:6 H:7 C:5 H:9 H:10O:8 H:4 O:11 H:12+ R37 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1O:2 H:12 H:4 C:3 H:6 H:7 C:5 H:9 H:10 O:8 O:11 R38 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1O:2 H:12 H:4 C:3 H:6 H:7 C:5 H:9 H:10 O:8 O:11 R39 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1 O:2 C:3 H:6H:7 C:5 H:9 H:10 O:8O:11 H:4H:12+ R40 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1 O:2 H:9 H:4 C:3 H:6 H:7 C:5 O:8 O:11 H:12 H:10 27 R41 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1 H:4 O:2 C:3 H:6 C:5 H:9 H:10 O:8 O:11 H:7H:12+ R42 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1H:4 C:3 H:6 C:5 H:9 H:10O:2 H:7 O:8 O:11 H:12+ R43 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1 O:2 H:4 O:11 H:12 C:3 H:6 H:7 C:5 H:9 H:10 O:8 + R44 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9 H:10 H:6 H:7 H:4 C:1 O:2 O:11 H:12 H:4 C:3 H:6 H:7 C:5 H:9 H:10 O:8 R45 C:1 O:2 C:3 C:5 O:8 O:11 H:12 H:9

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Catalysis

Ni-Catalyzed Arylbenzylation of Alkenylarenes. Kinetic Studies Reveal Autocatalysis by ZnX2 and 3-Fold Catalytic Rate Increase

Roshan K. Dhungana, Rishi R. Sapkota, Laura M. Wickham, Doleshwar Niroula, Bijay Shrestha, Ramesh Giri

Qi, J. Ying, X.-F. Wu, ACS Catal. 2019, 9 , 2977-2983. [4] a) W. Li, J. K. Boon, Y. Zhao, Chem. Sci. 2018, 9 , 600-607; b) S. Thapa, R. K. Dhungana, R. T. Magar, B. Shrestha, S. Kc, R. Giri, Chem. Sci. 2018, 9 , 904-909; c) O. Apolinar, V. T. Tran, N. Kim, M. A. Schmidt, J. Derosa, K. M. Engle, ACS Catal. 2020, 10, 14234-14239; d) P. Basnet, S. Kc, R. K. Dhungana, B. Shrestha, T. J. Boyle, R. Giri, J. Am. Chem. Soc. 2018, 140, 15586-15590; e) P. Basnet, R. K. Dhungana, S. Thapa, B. Shrestha, S. Kc, J. M. Sears, R. Giri, J. Am. Chem. Soc. 2018, 140, 7782-7786; f) R. K. Dhungana, S. Kc, P. Basnet, V. Aryal, L. J. Chesley, R. Giri, ACS Catal. 2019, 9

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Biological and Medicinal Chemistry

Chemical Synthesis and Immunological Evaluation of Cancer Vaccines Based on Ganglioside Antigens and α-Galactosylceramide

Cecilia Romanò, Hao Jiang, Sahar Tahvili, Peng Wei, Ulrik Bering Keiding, Gael Clergeaud, Jonas Rosager Henriksen, Thomas Lars Andresen, Anders Elias Hansen, Dennis Christensen, Mads Hartvig Clausen

Sialyl donor 8 was also prepared in 4 steps (38% global yield, SI) exclusively as the α-anomer with the key reaction being the SN2-like substitution of the corresponding glycosyl chloride with thiophenol under basic conditions. Conversely, sialyl donor 9 was synthesized from 8. First, deacetylation and amide hydrolysis were achieved by treatment with methanesulfonic acid under reflux, then the crude mixture was treated with readily synthesized O-benzylglycolic acid succinimidyl ester under basic conditions. Finally, the obtained compound was acetylated under standard conditions (Ac2O, pyridine) to afford sialyl donor 9 in 56% over three steps. Sialyl donors 8 and 9

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Theoretical and Computational Chemistry

First-Principles Plane-Wave-Based Exploration of Cathode and Anode Materials for Li and Na-ion Batteries

Christina Ertural, Ralf Stoffel, Peter Christian Müller, Christian Alexander Vogt, Richard Dronskowski

One may assume that the ionic char- acter of the Cs compounds and their inherent Madelung field leads to some extra stabilization, thereby also compensating the radical character. Having a look at the projected electronic DOS of the final structures (Fig. 9 ) reveals that, in case of vLi ′ [N(CN)2] and vNa ′ [N(CN)2], the unfavorable electronic state has disap- peared. The resulting dimerized compounds now show a wider band gap (Fig. 9 a, b) and no magnetization whatsoever. The projected DOS for vLi ′ Cs2[N(CN)2]3 and vNa ′ Cs2[N(CN)2]3 do not vary much from the one before structural relaxation (Fig. 9 d, e vs. Fig S6 d, e) due to a lack of structural change. 9 Figure 9

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Biological and Medicinal Chemistry

An expanded LUXendin color palette for GLP1R detection and visualization in vitro and in vivo

Julia Ast, Alissa N. Novak, Tom Podewin, Nicholas H. F. Fine, Ben Jones, Alejandra Tomas, Ramona Birke, Kilian Roßmann, Bettina Mathes, Jenny Eichhorst, Martin Lehmann, Amelia K. Linnemann, David J. Hodson, Johannes Broichhagen

Application of increasing doses of the 133 benchmark antagonist Exendin4(9 -39) inhibited GLP1-stimulated cAMP levels with a pIC50 = 134 7.0 ± 0.2 (Figure 1D). Confirming that the installed fluorophores did not alter potency of the 135 Exendin4(9 -39)-S39C backbone, LUXendin492 (pIC50 = 7.2 ± 0.2), LUXendin551 (pIC50 = 136 7.2 ± 0.1), LUXendin615 (pIC50 = 7.2 ± 0.1) and LUXendin762 (pIC50 = 7.0 ± 0.2) all inhibited 137 GLP1-stimulated (10 nM) cAMP levels in a manner equipotent to Exendin4(9 -39) (Figure 1E). 138 The pharmacology of Exendin4(9 -39)-S39C has previously been determined [12]. Thus, the 139 novel LUXendins show indistinguishable antagonistic properties from Exendin4(9

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Organic Chemistry

Umpolung Strategy for Arene C–H Etherification Leading to Functionalized Chromanes Enabled by I(III) N-Ligated Hypervalent Iodine Reagents

Myriam Mikhael, Wentao Guo, Dean J. Tantillo, Sarah E. Wengryniuk

Hamamoto, Y. Shiozaki, S. B. Cammerer, Y. Kita, Tetrahedron Lett. 2007, 63, 4052–4060. [6] K. Miyamoto, M. Hirobe, M. Saito, M. Shiro, M. Ochiai, Org. Lett. 2007, 9 , 1995–1998. [7] J. Alvarado, J. Fournier, A. Zakarian, Angew. Chem. Int. Ed. Engl. 2016, 55, 11625–11628. [8] a) B. T. Kelley, J. C. Walters, S. E. Wengryniuk, Org. Lett. 2016, 18, 1896−1899. b) J. C. Walters, A. F. Tierno, A. H. Dubin, and S. E. Wengryniuk, Eur. J. Org. Chem. 2018, 1460–1464. c) M. Mikhael, S. Adler, S. E. Wengryniuk, Org. Lett. 2019, 21, 5889–5893. [9

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Thermodynamic and structural insights into the repurposing of drugs that bind to SARS-CoV-2 main protease

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Cosolvent and Dynamic Effects in Binding Pocket Search by Docking Simulations

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Combination of pose and rank consensus in docking-based virtual screening: the best of both worlds

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Fast and Automated Identification of Reactions with Low Barriers: The Decomposition of 3-Hydroperoxypropanal

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Ni-Catalyzed Arylbenzylation of Alkenylarenes. Kinetic Studies Reveal Autocatalysis by ZnX2 and 3-Fold Catalytic Rate Increase

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Chemical Synthesis and Immunological Evaluation of Cancer Vaccines Based on Ganglioside Antigens and α-Galactosylceramide

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First-Principles Plane-Wave-Based Exploration of Cathode and Anode Materials for Li and Na-ion Batteries

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An expanded LUXendin color palette for GLP1R detection and visualization in vitro and in vivo

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Umpolung Strategy for Arene C–H Etherification Leading to Functionalized Chromanes Enabled by I(III) N-Ligated Hypervalent Iodine Reagents

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