Article
Chemistry, Medicinal
Torben Gutermuth, Jochen Sieg, Tim Stohn, Matthias Rarey
Summary: In many molecular modeling applications, proteins are commonly treated as single, rigid structures despite the importance of conformational flexibility. However, the handling of this flexibility remains challenging. This study analyzes the presence and usage of alternate locations (AltLocs) in protein structure files and proposes an algorithm to automatically handle AltLocs, allowing structure-based methods to consider alternative protein conformations. The software tool AltLocEnumerator can be used as a preprocessor to effectively utilize AltLocs. While the impact of handling AltLocs is difficult to showcase statistically, it has a substantial influence on a case-by-case basis, making it a valuable approach in many modeling scenarios.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Joel Ricci-Lopez, Sergio A. Aguila, Michael K. Gilson, Carlos A. Brizuela
Summary: The study demonstrates that using machine learning methods to process ensemble docking results can significantly improve the predictive power of structure-based virtual screening.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Medicinal
Pierpaolo Cordone, Hari K. Namballa, Bryant Muniz, Rajat K. Pal, Emilio Gallicchio, Wayne W. Harding
Summary: In this study, the effect of rigidification of the n-butyl linker region of tetrahydroisoquinoline-containing D3R ligands by incorporating an o-xylenyl motif was investigated. Rigidification with an o-xylenyl linker group was found to decrease D3R affinity and impact selectivity versus D2R for compounds with a specific pharmacophore group, but high affinity D3R ligands with different primary pharmacophore groups were identified. The study also revealed that D3R selectivity versus sigma R-2 is influenced by the benzamide secondary pharmacophore group, particularly with 4-substituted benzamides, and identified specific compounds as high affinity D3R ligands.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Hamed S. Hayatshahi, Robert R. Luedtke, Michelle Taylor, Peng-Jen Chen, Benjamin E. Blass, Jin Liu
Summary: Targeting the D3 dopamine receptor is a promising strategy for treating various disorders, but identifying selective pharmacotherapeutic agents is challenging due to structural similarities with the D2 dopamine receptor. Removing the thiophenearylamide portion of ligands consistently decreases affinity at the D3R. Molecular dynamics simulations show that D3R samples the open conformation more frequently than D2R, and ligands with conjoined orthosteric-allosteric binding moieties lead to the closed conformation being more prevalent in trajectories.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Multidisciplinary Sciences
Valeria Scardino, Juan I. Di Filippo, Claudio N. Cavasotto
Summary: A crucial component in structure-based drug discovery is high-quality three-dimensional structures of protein targets. When experimental structures are not available, homology modeling has been the preferred method. AlphaFold, an AI-based protein structure prediction method, has shown impressive accuracy. However, our evaluation using docking-based drug discovery revealed that AF models consistently performed worse compared to experimental structures. Post-modeling refinement strategies may be crucial to increase the chances of success.
Article
Biochemistry & Molecular Biology
Jessie Low Gan, Dhruv Kumar, Cynthia Chen, Bryn C. Taylor, Benjamin R. Jagger, Rommie E. Amaro, Christopher T. Lee
Summary: The discovery of new drugs is a time-consuming and expensive process. Methods like virtual screening have become popular research topics as they can filter out ineffective compounds from drug libraries. This study explores the use of receptor dynamics to improve ligand affinity rankings, and demonstrates the capabilities of high school students in computational drug discovery.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2022)
Article
Biochemistry & Molecular Biology
D. Sam Paul, P. Karthe
Summary: iMOLSDOCK is an induced-fit docking algorithm that uses the mutually orthogonal Latin squares (MOLS) sampling technique. Updates have been made to increase receptor flexibility, improve the scoring system, and speed up calculation. iMOLSDOCK has been benchmarked and validated with various datasets, and has shown improved performance in terms of ranking effectiveness and success rates compared to other docking tools.
JOURNAL OF MOLECULAR MODELING
(2023)
Article
Cardiac & Cardiovascular Systems
Andrew Kisling, Shannon Byrne, Rohan U. Parekh, Deepthy Melit-Thomas, Lisandra E. de Castro Bras, Robert M. Lust, Stefan Clemens, Srinivas Sriramula, Laxmansa C. Katwa
Summary: Evidence suggests the existence of an intracardiac dopaminergic system that plays a pivotal role in regulating cardiac function and fibrosis through G-protein coupled receptors, particularly mediated by dopamine receptor 3 (D3R). The study found that D3R in cardiac fibroblasts plays a crucial role in proliferation and migration, potentially mediating cardiac fibroblast function during the wound healing response. Loss of function in D3R resulted in attenuation of both proliferation and migration in response to scratch injury, and significantly increased the expression of Col3a1 in LV fibroblasts.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Ma'mon M. Hatmal, Omar Abuyaman, Mutasem Taha
Summary: In this study, the use of multiple docked poses for machine learning-based QSAR modelling was introduced to discover potential inhibitors of the serine protease enzyme TMPRSS2. Xgboost, SVM, and RF were found to be the best machine learners with testing set accuracies reaching 90%. Three potential hits were identified by scanning known untested FDA approved drugs against TMPRSS2. Subsequent molecular dynamics simulation and covalent docking supported the new computational approach's results.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Hugo Guterres, Sang-Jun Park, Han Zhang, Thomas Perone, Jongtaek Kim, Wonpil Im
Summary: Molecular docking is a popular computational tool in drug design, but has room for improvement. Molecular dynamics (MD) simulations of protein-ligand structures can enhance docking accuracy, and the CHARMM-GUI high-throughput simulator (HTS) is a tool for preparing MD simulation systems.
Article
Biology
Sarah Hall-Swan, Didier Devaurs, Mauricio M. Rigo, Dinler A. Antunes, Lydia E. Kavraki, Geancarlo Zanatta
Summary: An unprecedented research effort has been made in response to the COVID-19 pandemic, focusing on crystallographic structures of SARS-CoV-2 proteins and virtual screening for potential drug inhibitors. Addressing receptor flexibility, a computational tool called DINC-COVID has been implemented for ensemble docking with success in identifying alternative binding modes. This work highlights the importance of considering receptor flexibility in docking studies and provides a platform for new inhibitors against SARS-CoV-2 proteins.
COMPUTERS IN BIOLOGY AND MEDICINE
(2021)
Article
Chemistry, Medicinal
Sabrina Biselli, Merlin Bresinsky, Katharina Tropmann, Lisa Forster, Claudia Honisch, Armin Buschauer, Gunther Bernhardt, Steffen Pockes
Summary: A series of novel H2R and D3R agonists with high affinities and selectivity have been synthesized in this study, showing promising application prospects in in vitro experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Aluisio Marques da Fonseca, Neidelenio Baltazar Soares, Regilany Paulo Colares, Mauro Macedo de Oliveira, Larissa Santos Oliveira, Gabrielle Silva Marinho, Mira Raya Paula de Lima, Matheus Nunes da Rocha, Helcio Silva dos Santos, Emmanuel Silva Marinho
Summary: A new worldwide concern has emerged with the recent emergence of infections caused by Candida auris. This study evaluated the potential of two naphthoquinones, biflorin and bis-biflorin, isolated from Capraria biflora roots, as inhibitors of Candida auris polymerase. The simulation results showed that bis-biflorin exhibited the best interactions with Candida auris polymerase, while biflorin also demonstrated favorable coupling energy and pharmacokinetic properties.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Chemistry, Medicinal
Alessandro Bonifazi, Elizabeth Saab, Julie Sanchez, Antonina L. Nazarova, Saheem A. Zaidi, Khorshada Jahan, Vsevolod Katritch, Meritxell Canals, J. Robert Lane, Amy Hauck Newman
Summary: A new generation of dual-target μ opioid receptor (MOR) agonist/D3R antagonist/partial agonists was designed and synthesized. Through in vitro and in silico screening, new structural scaffolds were identified that achieved high affinity for MOR and D3R, improving receptor subtype selectivity and predicted blood-brain barrier permeability. Lead compounds have the potential for analgesic effects with reduced opioid-misuse liability via D3R antagonism.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Justin Tze-Yang Ng, Yaw Sing Tan
Summary: This study reports the development of a new method, accelerated ligand-mapping MD (aLMMD), for detecting challenging binding sites. The method is able to detect and sample cryptic pockets and occluded binding sites, and may serve as a general approach for structure-based drug design in proteins.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biochemistry & Molecular Biology
Polo C. -H. Lam, Ruben Abagyan, Maxim Totrov
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2019)
Article
Virology
Lily Liu, Liuzhe Li, Aubin Nanfack, Luzia M. Mayr, Sonal Soni, Adam Kohutnicki, Lucy Agyingi, Xiao-Hong Wang, Michael Tuen, Yongzhao Shao, Maxim Totrove, Susan Zolla-Pazner, Xian-Peng Kong, Ralf Duerr, Miroslaw K. Gorny
Article
Environmental Sciences
James M. Mutunga, Ming Ma, Qiao-Hong Chen, Joshua A. Hartsel, Dawn M. Wong, Sha Ding, Max Totrov, Paul R. Carlier, Jeffrey R. Bloomquist
INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH
(2019)
Article
Biochemistry & Molecular Biology
Polo C-H Lam, Ruben Abagyan, Maxim Totrov
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2019)
Article
Microbiology
Ruslan Tsivkovski, Maxim Totrov, Olga Lomovskaya
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Microbiology
Olga Lomovskaya, Ruslan Tsivkovski, Kirk Nelson, Debora Rubio-Aparicio, Dongxu Sun, Maxim Totrov, Michael N. Dudley
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Chemistry, Medicinal
Scott J. Hecker, K. Raja Reddy, Olga Lomovskaya, David C. Griffith, Debora Rubio-Aparicio, Kirk Nelson, Ruslan Tsivkovski, Dongxu Sun, Mojgan Sabet, Ziad Tarazi, Jonathan Parkinson, Maxim Totrov, Serge H. Boyer, Tomasz W. Glinka, Orville A. Pemberton, Yu Chen, Michael N. Dudley
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Microbiology
Orville A. Pemberton, Ruslan Tsivkovski, Maxim Totrov, Olga Lomovskaya, Yu Chen
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Virology
Rebecca L. Powell, Svenja Weiss, Alisa Fox, Xiaomei Liu, Vincenza Itri, Xunqing Jiang, Christina C. Luo, David A. Spencer, Shilpi Pandey, Tracy Cheever, Deborah H. Fuller, Maxim Totrov, Ann J. Hessell, Nancy L. Haigwood, Xiang-Peng Kong, Susan Zolla-Pazner
JOURNAL OF VIROLOGY
(2020)
Article
Microbiology
Kirk Nelson, Debora Rubio-Aparicio, Ruslan Tsivkovski, Dongxu Sun, Maxim Totrov, Michael Dudley, Olga Lomovskayaa
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2020)
Article
Biochemistry & Molecular Biology
Ian Miller, Max Totrov, Lioubov Korotchkina, Denis N. Kazyulkin, Andrei Gudkov, Sergey Korolev
Summary: Research on L1-EN has revealed that its sequence specificity and catalytic activity are influenced by the conformational properties of the preferred sequence. Unlike other nucleases, L1-EN does not bend the DNA helix, but rather causes 'compression' near the cleavage site, providing multiple advantages for retrotransposition. This work could potentially lead to the development of L1-EN inhibitors as anti-cancer and anti-aging therapeutics.
NUCLEIC ACIDS RESEARCH
(2021)
Review
Microbiology
Olga Lomovskaya, Ruslan Tsivkovski, Dongxu Sun, Raja Reddy, Maxim Totrov, Scott Hecker, David Griffith, Jeffery Loutit, Michael Dudley
Summary: QPX7728 is an ultra-broad-spectrum beta-lactamase inhibitor with potent inhibition against a wide range of clinically important beta-lactamases. It is minimally affected by common resistance mechanisms and shows broad coverage when combined with various beta-lactam antibiotics. The oral delivery option of QPX7728 also provides potential for application in combination products.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Chemistry, Medicinal
Hanan Almolhim, Sha Ding, Joshua H. Butler, Emily K. Bremers, Grant J. Butschek, Carla Slebodnick, Emilio F. Merino, Zaira Rizopoulos, Maxim Totrov, Maria B. Cassera, Paul R. Carlier
Summary: The tetrahydro-beta-carboline scaffold is a promising structure for the discovery of antimalarial agents. The molecule N2-acyl tetrahydro-beta-carboline GNFP-f-5009 ((+/-)-3b) was found through similarity searching and showed in vitro efficacy against P. falciparum. The enantiomer (R)-3b demonstrated superior pharmacological properties. However, oral efficacy was lacking in mouse testing, possibly due to unfavorable physicochemical properties.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Jopaul Mathew, Sha Ding, Kevin A. Kunz, Emily E. Stacy, Joshua H. Butler, Reagan S. Haney, Emilio F. Merino, Grant J. Butschek, Zaira Rizopoulos, Maxim Totrov, Maria B. Cassera, Paul R. Carlier
Summary: Virtual ligand screening using a pharmacophore derived from antimalarial MMV008138 led to the identification of TCMDC-140230 as a compound worth exploring. However, none of the four stereoisomers synthesized showed potent inhibition of Plasmodium falciparum growth, while a minor byproduct 7e exhibited strong in vitro antimalarial activity and was orally efficacious in an in vivo mouse model of malaria.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Eugene Raush, Ruben Abagyan, Maxim Totrov
Summary: This paper presents a GCNN-based method for learning and predicting statistical torsional profiles in small organic molecules. By training a specialized GCNN model, it accurately captures various torsional preferences and shows good agreement with quantum chemistry calculations. The application of this method in conformer generation further demonstrates its potential value.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)