Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis

Table 2

Complexation energy and its components for the training set of TMPKmt inhibitors: TMD1–TMD15.

Training set^a	𝑀𝑤^b	ΔΔ𝐻^cMM	ΔΔ𝐺^dsol	ΔΔ𝑇𝑆^evib	ΔΔ𝐺 compf	𝐾^expg𝑖
	(g · mol^−1)	(kcal · mol^−1)	(kcal · mol^−1)	(kcal · mol^−1)	(kcal · mol^−1)	(μM)
TMD1	228	0	0	0	0	1020
TMD2	246	−3.942	3.537	−1.968	−2.373	212
TMD3	354	−4.695	1.873	−2.196	−5.017	33
TMD4	306	−1.631	−3.514	−1.742	−6.887	5
TMD5	333	−5.880	1.212	−2.238	−6.906	7
TMD6	258	−3.461	3.613	−1.371	−1.220	238
TMD7	262	−5.157	7.239	−1.510	0.571	521
TMD8	242	3.496	−4.720	0.378	−0.847	230
TMD9	242	1.916	−1.255	0.786	1.447	1900
TMD10	256	−0.110	−3.672	−0.390	−4.172	57
TMD11	258	−21.643	22.028	−3.572	−3.187	45
TMD12	256	−1.323	0.216	−2.213	−3.320	41
TMD13	272	3.727	−3.906	−2.715	−2.894	393
TMD14	270	−3.988	6.637	−3.934	−1.286	156
TMD15	242	−6.706	9.914	−5.140	−1.932	27
Validation set	𝑀𝑤	ΔΔ𝐻MM	ΔΔ𝐺sol	ΔΔ𝑇𝑆vib	ΔΔ𝐺 comp	𝑝𝐾^pred𝑖/𝑝𝐾𝑖^exp
	[g · mol^−1]	[kcal · mol^−1]	[kcal · mol^−1]	[kcal · mol^−1]	[kcal · mol^−1]
TMV1	283	−1.641	−0.724	−1.807	−4.172	1.100
TMV2	258	−4.852	6.608	−0.372	1.385	0.899
TMV3	256	−4.166	2.479	−0.282	−1.969	1.296
TMV4	244	2.350	−4.156	−1.145	−2.951	0.899
TMV5	258	−4.310	3.609	−0.527	−1.228	1.164
TMV6	244	−3.999	2.689	−1.471	−2.780	1.134

aFor the chemical structures of the training set of inhibitors see Table 1.
^b𝑀_𝑤 is the molecular mass of the inhibitor.
^cΔΔ𝐻_MM is the relative enthalpic contribution to the Gibbs free energy change related to the protease-inhibitor complex formation derived by molecular mechanics (MM): ΔΔ𝐻_MM≅[𝐸_MM{PR:TMDx}−𝐸_MM{TMDx}]−[𝐸_MM{PR:TMD1}−𝐸_MM{TMD1}], TMD1—is the reference inhibitor;
^dΔΔ𝐺_solv is the relative solvation Gibbs free energy contribution to the Gibbs free energy change related to protease-inhibitor complex formation: ΔΔ𝐺_solv=[𝐺_solv{PR:TMDx}−𝐺_solv{TMDx}]−[𝐺_sol{PR:TMD1}−𝐺_sol{TMD1}];
^e−ΔΔ𝑇𝑆_vib is the relative entropic contribution of the inhibitor to the Gibbs free energy related to protease-inhibitor complex formation: ΔΔ𝑇𝑆_vib=[𝑇𝑆_vib{TMDx}_PR−𝑇𝑆_vib{TMDx}]−[𝑇𝑆_vib{TMD1}_PR−𝑇𝑆_vib{TMD1}];
^fΔΔ𝐺 _comp is the relative Gibbs free energy change related to the enzyme-inhibitor complex formation: ΔΔ𝐺_{𝑐𝑜𝑚𝑝}≅ΔΔ𝐻_MM+ΔΔ𝐺_solv−ΔΔ𝑇𝑆_vib.
^g𝐾_𝑖^exp is the experimental TMPKmt inhibition constant obtained from [15–17].
^hRatio of predicted and experimental inhibition constants 𝑝𝐾^pre_𝑖/𝑝𝐾_𝑖^exp⋅𝐾^pre_𝑖 was predicted from computed ΔΔ𝐺_comp using the regression equation for TMPKmt shown in Table 3.