Benjamin Patrick Brown, Ph.D., M.D.

Assistant Professor

benjamin.p.brown@vanderbilt.edu

Visit Lab Site


Faculty Appointments
Assistant Professor of Pharmacology
Education
M.D., Medicine, Vanderbilt University, Nashville, TennesseePh.D., Chemical and Physical Biology Program, Vanderbilt University, Nashville, TennesseeB.S., Chemistry and Neuroscience, Baldwin-Wallace College, Berea, Ohio
Research Description
I am developing a research program that integrates emerging techniques in artificial intelligence (AI) with traditional methods in informatics and biophysics for small molecule computer-aided drug discovery (CADD) and biomolecular design. In particular, we are interested in modeling, designing, and pharmacologically controlling protein dynamics using computer simulation. We apply our own methods in combination with other computational tools and in collaboration with experimental scientists to address fundamental biological problems in substance abuse and precision oncology. Specifically, we are working to develop mu-opioid receptor (µOR) partial agonists with selective recruitment of G-protein subtypes and to delineate the structural and dynamical basis of µOR engagement with different G-protein isoforms. Further, we perform simulations to understand and predict the effects of EGFR oncogenic mutations on conformational dynamics and measure how these changes alter intermolecular interactions with signaling partners and therapeutic agents. With respect to the development of methods, we are highly interested in developing and deploying AI for small molecule hit identification, pharmacokinetic liability predictions, and protein conformational sampling.

For details on specific projects, please see the lab website at https://www.bpbrownlab.org/research.
Research Keywords
computational chemistry; cheminformatics; computer-aided drug design; virtual screening; deep learning; artificial intelligence; computational structural biology; molecular dynamics
Publications
Brown BP, Stein RA, Meiler J, Mchaourab HS. Approximating Projections of Conformational Boltzmann Distributions with AlphaFold2 Predictions: Opportunities and Limitations. J Chem Theory Comput [print-electronic]. 2024 Feb 2/13/2024; 20(3): 1434-47. PMID: 38215214, PMCID: PMC10867840, DOI: 10.1021/acs.jctc.3c01081, ISSN: 1549-9626.

Shi X, Lingerak R, Herting CJ, Ge Y, Kim S, Toth P, Wang W, Brown BP, Meiler J, Sossey-Alaoui K, Buck M, Himanen J, Hambardzumyan D, Nikolov DB, Smith AW, Wang B. Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly. Science [print-electronic]. 2023 Dec; 382(6674): 1042-50. PMID: 37972196, PMCID: PMC11114627, DOI: 10.1126/science.adg5314, ISSN: 1095-9203.

Marín A, Mamun AA, Patel H, Akamatsu H, Ye D, Sudhan DR, Eli L, Marcelain K, Brown BP, Meiler J, Arteaga CL, Hanker AB. Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer. Cancer Res. 2023 Sep 9/15/2023; 83(18): 3145-58. PMID: 37404061, PMCID: PMC10530374, PII: 727589, DOI: 10.1158/0008-5472.CAN-22-3617, ISSN: 1538-7445.

Watson PR, Gupta S, Hosseinzadeh P, Brown BP, Baker D, Christianson DW. Macrocyclic Octapeptide Binding and Inferences on Protein Substrate Binding to Histone Deacetylase 6. ACS Chem Biol [print-electronic]. 2023 Apr 4/21/2023; 18(4): 959-68. PMID: 37027789, PMCID: PMC10130746, DOI: 10.1021/acschembio.3c00113, ISSN: 1554-8937.

Brown BP, Zhang YK, Kim S, Finneran P, Yan Y, Du Z, Kim J, Hartzler AL, LeNoue-Newton ML, Smith AW, Meiler J, Lovly CM. Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer. Proc Natl Acad Sci U S A [print-electronic]. 2022 Jul 7/26/2022; 119(30): e2206588119. PMID: 35867821, PMCID: PMC9335329, DOI: 10.1073/pnas.2206588119, ISSN: 1091-6490.

Bozhanova NG, Flyak AI, Brown BP, Ruiz SE, Salas J, Rho S, Bombardi RG, Myers L, Soto C, Bailey JR, Crowe JE, Bjorkman PJ, Meiler J. Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals. Nat Commun. 2022 Jun 6/8/2022; 13(1): 3178. PMID: 35676279, PMCID: PMC9177688, PII: 10.1038/s41467-022-30865-9, DOI: 10.1038/s41467-022-30865-9, ISSN: 2041-1723.

Brown BP, Vu O, Geanes AR, Kothiwale S, Butkiewicz M, Lowe EW, Mueller R, Pape R, Mendenhall J, Meiler J. Introduction to the BioChemical Library (BCL): An Application-Based Open-Source Toolkit for Integrated Cheminformatics and Machine Learning in Computer-Aided Drug Discovery. Front Pharmacol. 2022; 13: 833099. PMID: 35264967, PMCID: PMC8899505, PII: 833099, DOI: 10.3389/fphar.2022.833099, ISSN: 1663-9812.

Hanker AB, Brown BP, Meiler J, Marín A, Jayanthan HS, Ye D, Lin CC, Akamatsu H, Lee KM, Chatterjee S, Sudhan DR, Servetto A, Brewer MR, Koch JP, Sheehan JH, He J, Lalani AS, Arteaga CL. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity. Cancer Cell [print-electronic]. 2021 Aug 8/9/2021; 39(8): 1099-1114.e8-1114.e8. PMID: 34171264, PMCID: PMC8355076, PII: S1535-6108(21)00284-1, DOI: 10.1016/j.ccell.2021.06.001, ISSN: 1878-3686.

Du Z, Brown BP, Kim S, Ferguson D, Pavlick DC, Jayakumaran G, Benayed R, Gallant JN, Zhang YK, Yan Y, Red-Brewer M, Ali SM, Schrock AB, Zehir A, Ladanyi M, Smith AW, Meiler J, Lovly CM. Structure-function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting. Nat Commun. 2021 Mar 3/2/2021; 12(1): 1382. PMID: 33654076, PMCID: PMC7925532, PII: 10.1038/s41467-021-21613-6, DOI: 10.1038/s41467-021-21613-6, ISSN: 2041-1723.

Brown BP, Mendenhall J, Geanes AR, Meiler J. General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps. J Chem Inf Model [print-electronic]. 2021 Feb 2/22/2021; 61(2): 603-20. PMID: 33496578, PMCID: PMC7903419, DOI: 10.1021/acs.jcim.0c01001, ISSN: 1549-960X.

Mendenhall J, Brown BP, Kothiwale S, Meiler J. BCL::Conf: Improved Open-Source Knowledge-Based Conformation Sampling Using the Crystallography Open Database. J Chem Inf Model [print-electronic]. 2021 Jan 1/25/2021; 61(1): 189-201. PMID: 33351632, PMCID: PMC8130828, DOI: 10.1021/acs.jcim.0c01140, ISSN: 1549-960X.

Zeng D, Abzhanova A, Brown BP, Reiter NJ. Dissecting Monomer-Dimer Equilibrium of an RNase P Protein Provides Insight Into the Synergistic Flexibility of 5' Leader Pre-tRNA Recognition. Front Mol Biosci. 2021; 8: 730274. PMID: 34540901, PMCID: PMC8447495, PII: 730274, DOI: 10.3389/fmolb.2021.730274, ISSN: 2296-889X.

Bozhanova NG, Calcutt MW, Beavers WN, Brown BP, Skaar EP, Meiler J. Lipocalin Blc is a potential heme-binding protein. FEBS Lett [print-electronic]. 2021 Jan; 595(2): 206-19. PMID: 33210733, PMCID: PMC8177097, DOI: 10.1002/1873-3468.14001, ISSN: 1873-3468.

Sevy AM, Gilchuk IM, Brown BP, Bozhanova NG, Nargi R, Jensen M, Meiler J, Crowe JE. Computationally Designed Cyclic Peptides Derived from an Antibody Loop Increase Breadth of Binding for Influenza Variants. Structure [print-electronic]. 2020 Oct 10/6/2020; 28(10): 1114-1123.e4-1123.e4. PMID: 32610044, PMCID: PMC7544621, PII: S0969-2126(20)30124-6, DOI: 10.1016/j.str.2020.04.005, ISSN: 1878-4186.

Brown BP, Zhang YK, Westover D, Yan Y, Qiao H, Huang V, Du Z, Smith JA, Ross JS, Miller VA, Ali S, Bazhenova L, Schrock AB, Meiler J, Lovly CM. On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation. Clin Cancer Res [print-electronic]. 2019 Jun 6/1/2019; 25(11): 3341-51. PMID: 30796031, PMCID: PMC6548651, PII: 1078-0432.CCR-18-3829, DOI: 10.1158/1078-0432.CCR-18-3829, ISSN: 1557-3265.

Brown BP, Mendenhall J, Meiler J. BCL::MolAlign: Three-Dimensional Small Molecule Alignment for Pharmacophore Mapping. J Chem Inf Model [print-electronic]. 2019 Feb 2/25/2019; 59(2): 689-701. PMID: 30707580, PMCID: PMC6598199, DOI: 10.1021/acs.jcim.9b00020, ISSN: 1549-960X.

Zeng D, Brown BP, Voehler MW, Cai S, Reiter NJ. NMR resonance assignments of RNase P protein from Thermotoga maritima. Biomol NMR Assign [print-electronic]. 2018 Apr; 12(1): 183-7. PMID: 29450823, PMCID: PMC5871579, PII: 10.1007/s12104-018-9806-7, DOI: 10.1007/s12104-018-9806-7, ISSN: 1874-270X.

Brown BP, Kang SC, Gawelek K, Zacharias RA, Anderson SR, Turner CP, Morris JK. In vivo and in vitro ketamine exposure exhibits a dose-dependent induction of activity-dependent neuroprotective protein in rat neurons. Neuroscience [print-electronic]. 2015 Apr 4/2/2015; 290: 31-40. PMID: 25595994, PII: S0306-4522(15)00051-2, DOI: 10.1016/j.neuroscience.2014.12.076, ISSN: 1873-7544.

Lang BT, Cregg JM, DePaul MA, Tran AP, Xu K, Dyck SM, Madalena KM, Brown BP, Weng YL, Li S, Karimi-Abdolrezaee S, Busch SA, Shen Y, Silver J. Modulation of the proteoglycan receptor PTPs promotes recovery after spinal cord injury. Nature [print-electronic]. 2015 Feb 2/19/2015; 518(7539): 404-8. PMID: 25470046, PMCID: PMC4336236, PII: nature13974, DOI: 10.1038/nature13974, ISSN: 1476-4687.