Traditionally, the thermodynamic values of affinity are considered as the main criterion for the development of new drugs. Usually, these values for drugs are measured in vitro at steady concentrations of the receptor and ligand, which are differed from in vivo environment. Recent studies have shown that the kinetics of the process of drug binding to its receptor make significant contribution in the drug effectiveness. This has increased attention in characterizing and predicting the rate constants of association and dissociation of the receptor ligand at the stage of preclinical studies of drug candidates. A drug with a long residence time can determine ligand-receptor selectivity (kinetic selectivity), maintain pharmacological activity of the drug at its low concentration in vivo. The paper discusses the theoretical basis of protein-ligand binding, molecular determinants that control the kinetics of the drug-receptor binding. Understanding the molecular features underlying the kinetics of receptor-ligand binding will contribute to the rational design of drugs with desired properties.
Cook D., Brown D., Alexander R., March R., Morgan P., Satterthwaite G., Pangalos M.N. (2014) Nat. Rev. Drug Discovery, 13, 419-431. CrossRef Scholar google search
Copeland R.A., Williams J.M., Giannaras J., Nurnberg S., Covington M., Pinto D., Pick S., Trzaskos J.M. (1994) Proc. Natl. Acad. Sci. USA, 91, 11202-11206. CrossRef Scholar google search
Daryaee F., Chang A., Schiebel J., Lu Y., Zhang Z., Kapilashrami K., Walker S.G., Kisker C., Sotriffer C.A., Fisher S.L., Tonge P.J. (2016) Chem. Sci., 7, 5945-5954. CrossRef Scholar google search
Gooljarsingh L.T., Fernandes C., Yan K., Zhang H., Grooms M., Johanson K., Sinnamon R.H., Kirkpatrick R.B., Kerrigan J., Lewis T., Arnone M., King A.J., Lai Z., Copeland R.A., Tummino P.J. (2006) Proc. Natl. Acad. Sci. USA, 103, 7625-7630. CrossRef Scholar google search
Guo D., Mulder-Kriege T., IJzerman A.P., Heitman L.H. (2012) Br. J. Pharmacol., 166, 1846-1859. CrossRef Scholar google search
Lu H., England K., am Ende C., Truglio J.J., Luckner S., Reddy B.G., Marlenee N.L., Knudson S.E., Knudson D.L., Bowen R.A., Kisker C., Slayden R.A., Tonge P.J. (2009) ACS Chem. Biol., 4, 221-231. CrossRef Scholar google search
van Aller G.S., Pappalardi M.B., Ott H.M., Diaz E., Brandt M., Schwartz B.J., Miller W.H., Dhanak D., McCabe M.T., Verma S.K., Creasy C.L., Tummino P.J., Kruger R.G. (2014) ACS Chem. Biol., 9, 622-629. CrossRef Scholar google search
Kruse A.C., Hu J., Pan A.C., Arlow D.H., Rosenbaum D.M., Rosemond E., Green H.F., Liu T., Chae P.S., Dror R.O., Shaw D.E., Weis W.I., Wess J., Kobilka B.K. (2012) Nature, 482, 552-556. CrossRef Scholar google search
Sykes D.A., Moore H., Stott L., Holliday N., Javitch J.A., Lane J.R., Charlton S.J. (2017) Nat. Commun., 8, 763. CrossRef Scholar google search
Chang A., Schiebel J., Yu W., Bommineni G.R., Pan P., Baxter M.V., Khanna A., Sotriffer C.A., Kisker C., Tonge P.J. (2013) Biochemistry, 52, 4217-4228. CrossRef Scholar google search
Schuetz D.A., de Witte W.E.A., Wong Y.C., Knasmueller B., Richter L., Kokh D.B., Sadiq S.K., Bosma R., Nederpelt I., Heitman L.H. et al. (2017) Drug Discov. Today, 22, 896-911. CrossRef Scholar google search
Gao Y., Davies S.P., Augustin M., Woodward A., Patel U.A., Kovelman R., Harvey K.J. (2013) Biochem. J., 451, 313-328. CrossRef Scholar google search
Janssen A.P.A., Grimm S.H., Wijdeven R.H.M., Lenselink E.B., Neefjes J., van Boeckel C.A.A., van Westen G.J.P., van der Stelt M. (2019) J. Chem. Inf. Model., 59, 1221-1229. CrossRef Scholar google search
Miduturu C.V., Deng X., Kwiatkowski N., Yang W., Brault L., Filippakopoulos P., Chung E., Yang Q., Schwaller J., Knapp S., King R.W., Lee J.D., Herrgard S., Zarrinkar P., Gray N.S. (2011) Chem. Biol., 18, 868-879. CrossRef Scholar google search
Ayaz P., Andres D., Kwiatkowski D.A., Kolbe C.C., Lienau P., Siemeister G., Lucking U., Stegmann C.M. (2016) ACS Chem. Biol., 11, 1710-1719. CrossRef Scholar google search
de Witte W.E.A., Danhof M., van der Graaf P.H., de Lange E.C. (2016) Trends Pharmacol. Sci., 37, 831-842. CrossRef Scholar google search
Sykes D.A., Dowling M.R., Leighton-Davies J., Kent T.C., Fawcett L., Renard E., Trifilieff A., Charlton S.J. (2012) J. Pharmacol. Exp. Ther., 343, 520-528. CrossRef Scholar google search
Tautermann C.S., Kiechle T., Seeliger D., Diehl S., Wex E., Banholzer R., Gantner F., Pieper M.P., Casarosa P. (2013) J. Med. Chem., 56, 8746-8756. CrossRef Scholar google search
Walkup G.K., You Z., Ross P.L., Allen E.K., Daryaee F., Hale M.R., O'Donnell J., Ehmann D.E., Schuck V.J., Buurman E.T., Choy A.L., Hajec L., Murphy-Benenato K., Marone V., Patey S.A., Grosser L.A., Johnstone M., Walker S.G., Tonge P.J., Fisher S.L. (2015) Nat. Chem. Biol., 11, 416-423. CrossRef Scholar google search
Dierynck I., De Wit M., Gustin E., Keuleers I., Vandersmissen J., Hallenberger S., Hertogs K. (2007) J. Virol., 81, 13845-13851. CrossRef Scholar google search
Maschera B., Darby G., Palú G., Wright L.L., Tisdale M., Myers R., Blair E.D., Furfine E.S. (1996) J. Biol. Chem., 271, 33231-33235. CrossRef Scholar google search
Hyre D.E., Le Trong I., Merritt E.A., Eccleston J.F., Green N.M., Stenkamp R.E., Stayton P.S. (2006) Protein Sci., 15, 459-467. Scholar google search
Basavapathruni A., Jin L., Daigle S.R., Majer C.R., Therkelsen C.A., Wigle T.J., Kuntz K.W., Chesworth R., Pollock R.M., Scott M.P., Moyer M.P., Richon V.M., Copeland R.A., Olhava E.J. (2012) Chem. Biol. Drug Des., 80, 971-980. CrossRef Scholar google search
Hsiou Y., Ding J., Das K., Clark A.D. Jr., Boyer P.L., Lewi P., Janssen P.A., Kleim J.P., Rösner M., Hughes S.H., Arnold E. (2001) J. Mol. Biol., 309, 437-445. CrossRef Scholar google search
Lindberg J., Sigurdsson S., Löwgren S., Andersson H.O., Sahlberg C., Noréen R., Fridborg K., Zhang H., Unge T. (2002) Eur. J. Biochem., 269, 1670-1677. CrossRef Scholar google search
Han S., Zaniewski R.P., Marr E.S., Lacey B.M., Tomaras A.P., Evdokimov A., Miller J.R., Shanmugasundaram V. (2010) Proc. Natl. Acad. Sci. USA, 107, 22002-22007. CrossRef Scholar google search
Liu L., Michelsen K., Kitova E.N., Schnier P.D., Klassen J.S. (2010) J. Am. Chem. Soc., 132, 17658-17660. CrossRef Scholar google search
Schuetz D.A., Richter L., Amaral M., Grandits M., Grädler U., Musil D., Buchstaller H.P., Eggenweiler H.M., Frech M., Ecker G.F. (2018) J. Med. Chem., 61, 4397-4411. CrossRef Scholar google search
Cramer J., Krimmer S.G., Fridh V., Wulsdorf T., Karlsson R., Heine A., Klebe G. (2017) ACS Chem. Biol., 12, 225-233. CrossRef Scholar google search
Lewandowicz A., Tyler P., Evans G.B., Furneaux R.H., Schramm V.L. (2003) J. Biol. Chem., 278, 31465-31468. CrossRef Scholar google search
Bryant J., Post J.M., Alexander S., Wang Y.X., Kent L., Schirm S., Tseng J.L., Subramanyam B., Buckman B., Islam I., Yuan S., Sullivan M.E., Snider M., Morser J. (2008) Thromb. Res., 122, 523-532. CrossRef Scholar google search
